To see the other types of publications on this topic, follow the link: Epigenetic reprograming.
Journal articles on the topic 'Epigenetic reprograming'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Epigenetic reprograming.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Lameirinhas, Ana, Vera Miranda-Gonçalves, Rui Henrique, and Carmen Jerónimo. "The Complex Interplay between Metabolic Reprogramming and Epigenetic Alterations in Renal Cell Carcinoma." Genes 10, no. 4 (April 2, 2019): 264. http://dx.doi.org/10.3390/genes10040264.
Full textAbstract:
Renal cell carcinoma (RCC) is the most common malignancy affecting the kidney. Current therapies are mostly curative for localized disease, but do not completely preclude recurrence and metastization. Thus, it is imperative to develop new therapeutic strategies based on RCC biological properties. Presently, metabolic reprograming and epigenetic alterations are recognized cancer hallmarks and their interactions are still in its infancy concerning RCC. In this review, we explore RCC biology, highlighting genetic and epigenetic alterations that contribute to metabolic deregulation of tumor cells, including high glycolytic phenotype (Warburg effect). Moreover, we critically discuss available data concerning epigenetic enzymes’ regulation by aberrant metabolite accumulation and their consequences in RCC emergence and progression. Finally, we emphasize the clinical relevance of uncovering novel therapeutic targets based on epigenetic reprograming by metabolic features to improve treatment and survival of RCC patients.
2
Aguirre-Vázquez, Alain, Luis A. Salazar-Olivo, Xóchitl Flores-Ponce, Ana L. Arriaga-Guerrero, Dariela Garza-Rodríguez, María E. Camacho-Moll, Iván Velasco, Fabiola Castorena-Torres, Nidheesh Dadheech, and Mario Bermúdez de León. "5-Aza-2′-Deoxycytidine and Valproic Acid in Combination with CHIR99021 and A83-01 Induce Pluripotency Genes Expression in Human Adult Somatic Cells." Molecules 26, no. 7 (March 29, 2021): 1909. http://dx.doi.org/10.3390/molecules26071909.
Full textAbstract:
A generation of induced pluripotent stem cells (iPSC) by ectopic expression of OCT4, SOX2, KLF4, and c-MYC has established promising opportunities for stem cell research, drug discovery, and disease modeling. While this forced genetic expression represents an advantage, there will always be an issue with genomic instability and transient pluripotency genes reactivation that might preclude their clinical application. During the reprogramming process, a somatic cell must undergo several epigenetic modifications to induce groups of genes capable of reactivating the endogenous pluripotency core. Here, looking to increase the reprograming efficiency in somatic cells, we evaluated the effect of epigenetic molecules 5-aza-2′-deoxycytidine (5AZ) and valproic acid (VPA) and two small molecules reported as reprogramming enhancers, CHIR99021 and A83-01, on the expression of pluripotency genes and the methylation profile of the OCT4 promoter in a human dermal fibroblasts cell strain. The addition of this cocktail to culture medium increased the expression of OCT4, SOX2, and KLF4 expression by 2.1-fold, 8.5-fold, and 2-fold, respectively, with respect to controls; concomitantly, a reduction in methylated CpG sites in OCT4 promoter region was observed. The epigenetic cocktail also induced the expression of the metastasis-associated gene S100A4. However, the epigenetic cocktail did not induce the morphological changes characteristic of the reprogramming process. In summary, 5AZ, VPA, CHIR99021, and A83-01 induced the expression of OCT4 and SOX2, two critical genes for iPSC. Future studies will allow us to precise the mechanisms by which these compounds exert their reprogramming effects.
3
Habel, Nadia, Najla El-Hachem, Frédéric Soysouvanh, Hanene Hadhiri-Bzioueche, Serena Giuliano, Sophie Nguyen, Pavel Horák, et al. "FBXO32 links ubiquitination to epigenetic reprograming of melanoma cells." Cell Death & Differentiation 28, no. 6 (January 18, 2021): 1837–48. http://dx.doi.org/10.1038/s41418-020-00710-x.
Full textAbstract:
AbstractUbiquitination by serving as a major degradation signal of proteins, but also by controlling protein functioning and localization, plays critical roles in most key cellular processes. Here, we show that MITF, the master transcription factor in melanocytes, controls ubiquitination in melanoma cells. We identified FBXO32, a component of the SCF E3 ligase complex as a new MITF target gene. FBXO32 favors melanoma cell migration, proliferation, and tumor development in vivo. Transcriptomic analysis shows that FBXO32 knockdown induces a global change in melanoma gene expression profile. These include the inhibition of CDK6 in agreement with an inhibition of cell proliferation and invasion upon FBXO32 silencing. Furthermore, proteomic analysis identifies SMARC4, a component of the chromatin remodeling complexes BAF/PBAF, as a FBXO32 partner. FBXO32 and SMARCA4 co-localize at loci regulated by FBXO32, such as CDK6 suggesting that FBXO32 controls transcription through the regulation of chromatin remodeling complex activity. FBXO32 and SMARCA4 are the components of a molecular cascade, linking MITF to epigenetics, in melanoma cells.
4
Bui, L. C., A. V. Evsikov, D. R. Khan, C. Archilla, N. Peynot, A. Hénaut, D. Le Bourhis, X. Vignon, J. P. Renard, and V. Duranthon. "Retrotransposon expression as a defining event of genome reprograming in fertilized and cloned bovine embryos." REPRODUCTION 138, no. 2 (August 2009): 289–99. http://dx.doi.org/10.1530/rep-09-0042.
Full textAbstract:
Genome reprograming is the ability of a nucleus to modify its epigenetic characteristics and gene expression pattern when placed in a new environment. Low efficiency of mammalian cloning is attributed to the incomplete and aberrant nature of genome reprograming after somatic cell nuclear transfer (SCNT) in oocytes. To date, the aspects of genome reprograming critical for full-term development after SCNT remain poorly understood. To identify the key elements of this process, changes in gene expression during maternal-to-embryonic transition in normal bovine embryos and changes in gene expression between donor cells and SCNT embryos were compared using a new cDNA array dedicated to embryonic genome transcriptional activation in the bovine. Three groups of transcripts were mostly affected during somatic reprograming: endogenous terminal repeat (LTR) retrotransposons and mitochondrial transcripts were up-regulated, while genes encoding ribosomal proteins were downregulated. These unexpected data demonstrate specific categories of transcripts most sensitive to somatic reprograming and likely affecting viability of SCNT embryos. Importantly, massive transcriptional activation of LTR retrotransposons resulted in similar levels of their transcripts in SCNT and fertilized embryos. Taken together, these results open a new avenue in the quest to understand nuclear reprograming driven by oocyte cytoplasm.
5
Pilsner, J. Richard, Mikhail Parker, Oleg Sergeyev, and Alexander Suvorov. "Spermatogenesis disruption by dioxins: Epigenetic reprograming and windows of susceptibility." Reproductive Toxicology 69 (April 2017): 221–29. http://dx.doi.org/10.1016/j.reprotox.2017.03.002.
Full text
6
Merino, Aimee, Bin Zhang, Philip Dougherty, Xianghua Luo, Jinhua Wang, Bruce R. Blazar, Jeffrey S. Miller, and Frank Cichocki. "Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming." Journal of Clinical Investigation 129, no. 9 (August 12, 2019): 3770–85. http://dx.doi.org/10.1172/jci125916.
Full text
7
Zhang, Zhiren, Yanhui Zhai, Xiaoling Ma, Sheng Zhang, Xinglan An, Hao Yu, and Ziyi Li. "Down-Regulation of H3K4me3 by MM-102 Facilitates Epigenetic Reprogramming of Porcine Somatic Cell Nuclear Transfer Embryos." Cellular Physiology and Biochemistry 45, no. 4 (2018): 1529–40. http://dx.doi.org/10.1159/000487579.
Full textAbstract:
Background/Aims: Aberrantly high levels of H3K4me3, caused by incomplete epigenetic reprogramming, likely cause a low efficiency of somatic cell nuclear transfer (SCNT). Smal molecule inhibitors aimed at epigenetic modification can be used to improve porcine SCNT embryo development. In this study, we examined the effects of MM-102, an H3K4 histone methyltransferase inhibitor, on porcine SCNT preimplantation embryos to investigate the mechanism by which H3K4 methylation regulated global epigenetic reprograming during SCNT. Methods: MM-102 was added to the SCNT embryos culture system and the global levels of various epigenetic modifications were measured by immunofluorescence (IF) staining and were quantified by Image J software. Relative genes expression levels were detected by quantitative real-time PCR. Results: MM-102 (75 μM) treatment reduced global H3K4, H3K9 methylation and 5mC levels especially at the zygotic gene activation (ZGA) and blastocyst stages. MM-102 treatment mainly down-regulated a series of DNA and histone methyltransferases, and up-regulated a number of hitone acetyltransferases and transcriptional activators. Furthermore, MM-102 treatment positively regulated the mRNA expression of genes related to pluripotency (OCT4, NANOG, CDX2) and apoptosis (BCL2). Conclusion: Down-regulation of H3K4me3 with MM-102 rescued aberrant gene expression patterns of a series of epigenetic chromatin modification enzymes, pluripotent and apoptotic genes at the ZGA and blastocyst stages, thereby greatly improving porcine SCNT efficiency and blastocyst quality, making them more similar to in vivo embryos (IVV).
8
Amsalem, Zohar, Tasleem Arif, Anna Shteinfer-Kuzmine, Vered Chalifa-Caspi, and Varda Shoshan-Barmatz. "The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link." Cancers 12, no. 4 (April 22, 2020): 1031. http://dx.doi.org/10.3390/cancers12041031.
Full textAbstract:
Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial–mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism–epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics.
9
Mani, Sneha, and Monica Mainigi. "Embryo Culture Conditions and the Epigenome." Seminars in Reproductive Medicine 36, no. 03/04 (May 2018): 211–20. http://dx.doi.org/10.1055/s-0038-1675777.
Full textAbstract:
AbstractAssisted reproductive technologies (ARTs) lead to an increased risk for pregnancy complications, congenital abnormalities, and specific imprinting disorders. Epigenetic dysfunction is thought to be one common mechanism which may be affecting these outcomes. The timing of multiple ART interventions overlaps with developmental time periods that are particularly vulnerable to epigenetic change. In vitro embryo culture is known to impact blastocyst development, in vitro fertilization (IVF) success rates, as well as neonatal outcomes. Embryo culture, in contrast to other procedures involved in ART, is obligatory, and has the highest potential for causing alterations in epigenetic reprograming. In this review, we summarize progress that has been made in exploring the effects of embryo culture, culture media, and oxygen tension on epigenetic regulation in the developing embryo. In humans, it is difficult to isolate the role of embryo culture on epigenetic perturbations. Therefore, additional well-controlled animal studies isolating individual exposures are necessary to minimize the epigenetic effects of modifiable factors utilized during ART. Findings from these studies will likely not only improve IVF success rates but also reduce the risk of adverse perinatal outcomes.
10
Byrne, Kristen A., Hamid Beiki, Christopher K. Tuggle, and Crystal L. Loving. "β-glucan induced training and tolerance: alterations to primary monocytes." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 59.17. http://dx.doi.org/10.4049/jimmunol.200.supp.59.17.
Full textAbstract:
Abstract In mice and humans, exposure to β-glucan can induce epigenetic reprograming in monocytes resulting in enhanced responses to heterologous agonists. Epigenetic reprograming is the basis for innate memory, which includes both decreased immune responsiveness (innate tolerance) and increased responsiveness (innate training). As a valuable food animal and medically relevant species, we sought to understand the phenotypic and mechanistic alterations induced by β-glucan on swine cells to develop methods to enhance health while limiting antibiotic usage. Thus, primary porcine monocytes were stimulated with β-glucan from S. cerevisiae or C. albicans, rested for 5 d, and then restimulated with lipopolysaccharide (LPS; TLR 4 agonist) or Pam3CSK4 (synthetic triacylated lipopeptide; TLR 2 agonist) to determine trained or tolerant phenotype (increase or decrease in cytokine production relative to unstimulated controls). Zymosan (β-glucan from S. cerevisiae) primed monocytes exhibited a tolerant phenotype (decreased IL-1β and TNF-α production compared to controls) when restimulated with LPS or Pam3CSK4. However, β-glucan from C. albicans (the primary β-glucan used in mouse and human studies) primed porcine monocytes for increased cytokine production after LPS and Pam3CSK4 stimulation, an indication of trained immunity. Epigenetic analysis of the accessibility of the genome to transposase (ATAC-sequencing) showed changes in promoter peaks with treatment, providing insight into mechanisms of tolerance versus training. These data indicate that β-glucan can induce both training and tolerance in porcine monocytes, but the source and purity of β-glucan likely impacts innate memory.
11
Norman, Allison R., Grace Anne Ward, Caitlin C. Zebley, and Ben A. Youngblood. "Effects of targeted epigenetic modifications on T – cell reprogramming." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 148.09. http://dx.doi.org/10.4049/jimmunol.210.supp.148.09.
Full textAbstract:
Abstract Over the last decade there have been huge advances in DNA sequencing technology, allowing cancer patients to undergo genomic diagnosis within days of admission. Building upon genomic sequencing, epigenomic profiling approaches of tumor and infiltrating lymphocytes inform on the stage of the disease and immune response, but interpretation of these data remains hindered by issues of heterogeneity. Epigenetic programs, such as DNA methylation, play a vital role in the regulation of CD8+ T – cell development and differentiation. Here, we will investigate the effects of targeted epigenetic mechanisms on the function of effector memory T – cells. Hypomethylating agents, such as Decitabine, have been extensively used in myeloid malignancies including Acute Myeloid Leukemia and Myelodysplastic Syndromes; however, the impacts on T – cells have not been well studied. We hypothesize that the utilization of these epigenetic modifications will alter the function and phenotypic characteristics of the effector memory T – cells. These results will lead to new approaches for reprograming effector memory T – cells via removal of repressive DNA methylation. The outcome of this study will provide novel insight into our understanding of the epigenetic regulation of T – cells function; especially, how DNA methylation programs instilled during differentiation could be modified to improve T – cells function.
12
Anderson, Juan, Mariah Delgado, Malcolm Lovett, Maya Saunders, Geovannie Lake, Samuel Darko, Rose M. Stiffin, et al. "Abstract 859: Development of non-smoking lung cancers by indoor carcinogenic aerosols through epigenetic reprogramming of lung stem cells: Bioinformatics and artificial intelligence analysis." Cancer Research 84, no. 6_Supplement (March 22, 2024): 859. http://dx.doi.org/10.1158/1538-7445.am2024-859.
Full textAbstract:
Abstract Several scientific studies discovered the toxic effects of indoor aerosols on different organs’ adult stem cells of the human body. The most importantly, the indoor toxic aerosols comprised of numerous carcinogens namely, sodium dodecyl sulfate, phthalic acids from floor cleaners, formaldehyde, acetaldehyde, benzene, toluene, ethyl benzene, xylenes, from air fresheners, Hydramethylnon, Pyrethrins, imiprothrin, cypermethrin, tetramethrin, prallethrin and permethrin from ant and roach Killer. However, there was a lack of analysis revealing the mechanism of toxic effects and epigenetic reprogramming of human lung stem cells and development of non-smoking lung cancers. In this study, we analyzed the toxic effects of these chemicals and the mechanism of epigenetic reprograming on lung epithelial cells using Comparative Toxico-genomics Database (CTD), database of Environmental Health Perspectives (EHP), National Institute of Environmental Health Sciences (NIEHS), Google search browser with generative artificial intelligence (AI) and other biological informatics methods (Reactome, Cytoscape PSICQUIC services, and ChEMBL database). We observed from CTD analysis that the chemical gene interactions as risk factors from indoor aerosols showed transcriptionally highly expressed of 31 common genes, by phthalic acids, sodium dodecyl sulfate, from the total of 1347 genes, 107 common genes by formaldehyde, acetaldehyde from the total of 4193 genes and all other toxic ingredients of indoor aerosols. The epigenetic mechanism of histone modifications (H3K4me3, H3K9me3, H3K27me3, H3K27ac, H3K36me3, H3K4me1, Hsa-mir-1301 of lung epithelial, and miRNAs have been revealed by NIH Roadmap Epigenomics Mapping Consortium and the lung tissue arrays were analyzed with AI and matplotlib program. The heterogenic adult stem cell reprogramming is regulated by epigenetic bivalent histone modifications at transcript starts sequences (TSS) of target genes and our current study revealed that CD44, CD80, ALDH2, ALDH3A1, ALDH3B2 are epigenetically reprogrammed with close interaction of other genes by these toxic ingredients of indoor aerosols. Therefore, our results are significant for the carcinogenic effects of indoor aerosols causing for development of lung cancer epigenetically, which may give a clue for the prevention and treatment of nonsmoking lung cancer. Citation Format: Juan Anderson, Mariah Delgado, Malcolm Lovett, Maya Saunders, Geovannie Lake, Samuel Darko, Rose M. Stiffin, Ayivi Huisso, Marilyn Sherman, Latoya Appleton, Amalya Mihnea, Swarnava Das, Mohammad M. Algahtani, Ravi Vadapalli, Biswarup Basu, Arunima Biswas, Noor Neha, Madhumita Das, Marco A. Ruiz, Mayur Doke, Jayanta K. Das. Development of non-smoking lung cancers by indoor carcinogenic aerosols through epigenetic reprogramming of lung stem cells: Bioinformatics and artificial intelligence analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 859.
13
Li, Mingli, and Chun-Wei Chen. "Epigenetic and Transcriptional Signaling in Ewing Sarcoma—Disease Etiology and Therapeutic Opportunities." Biomedicines 10, no. 6 (June 5, 2022): 1325. http://dx.doi.org/10.3390/biomedicines10061325.
Full textAbstract:
Ewing sarcoma (EwS), a type of bone and soft tissue tumor, is mainly driven by the expression of the fusion protein EWSR1-FLI1. Upon binding to chromatin, EWSR1-FLI1 reprograms the epigenetic state, alters gene expression, and thus leads to tumorigenesis. Considerable studies have investigated the epigenomic and transcriptomic profiling of EwS. Nevertheless, a comprehensive view of therapeutic targets is still lacking. This review discusses the epigenetic and transcriptional alterations reported in EwS. Specifically, we discuss the binding characteristics of EWSR1-FLI1 on chromatin, the mechanisms of EWSR1-FLI1 in reprograming epigenome, and EWSR1-FLI1-induced transcriptional alterations. Moreover, we summarize the chemical, RNAi, and CRISPR-cas9 high throughput screens conducted in EwS with the goal of assisting in the development of novel therapies to treat this aggressive disease.
14
Kelly, Rebeca, Diego Aviles, Catriona Krisulevicz, Krystal Hunter, Lauren Krill, David Warshal, and Olga Ostrovsky. "The Effects of Natural Epigenetic Therapies in 3D Ovarian Cancer and Patient-Derived Tumor Explants: New Avenues in Regulating the Cancer Secretome." Biomolecules 13, no. 7 (July 1, 2023): 1066. http://dx.doi.org/10.3390/biom13071066.
Full textAbstract:
High mortality rates in ovarian cancer have been linked to recurrence, metastasis, and chemoresistant disease, which are known to involve not only genetic changes but also epigenetic aberrations. In ovarian cancer, adipose-derived stem cells from the omentum (O-ASCs) play a crucial role in supporting the tumor and its tumorigenic microenvironment, further propagating epigenetic abnormalities and dissemination of the disease. Epigallocatechin gallate (EGCG), a DNA methyltransferase inhibitor derived from green tea, and Indole-3-carbinol (I3C), a histone deacetylase inhibitor from cruciferous vegetables, carry promising effects in reprograming aberrant epigenetic modifications in cancer. Therefore, we demonstrate the action of these diet-derived compounds in suppressing the growth of 3D ovarian cancer spheroids or organoids as well as post-treatment cancer recovery through proliferation, migration, invasion, and colony formation assays when compared to the synthetic epigenetic compound Panobinostat with or without standard chemotherapy. Finally, given the regulatory role of the secretome in growth, metastasis, chemoresistance, and relapse of disease, we demonstrate that natural epigenetic compounds can regulate the secretion of protumorigenic growth factors, cytokines, extracellular matrix components, and immunoregulatory markers in human ovarian cancer specimens. While further studies are needed, our results suggest that these treatments could be considered in the future as adjuncts to standard chemotherapy, improving efficiency and patient outcomes.
15
Gehrmann, Ulf, Marianne Burbage, Elina Zueva, Christel Goudot, Cyril Esnault, Mengliang Ye, Jean-Marie Carpier, et al. "Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation." Proceedings of the National Academy of Sciences 116, no. 51 (November 27, 2019): 25839–49. http://dx.doi.org/10.1073/pnas.1901639116.
Full textAbstract:
Naive CD4+T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms that install and maintain these programs. Here, we use mice defective for different components of heterochromatin-dependent gene silencing to investigate the epigenetic control of CD4+T cell plasticity. We show that, upon T cell receptor (TCR) engagement, naive and regulatory T cells defective for TRIM28 (an epigenetic adaptor for histone binding modules) or for heterochromatin protein 1 β and γ isoforms (HP1β/γ, 2 histone-binding factors involved in gene silencing) fail to effectively signal through the PI3K–AKT–mTOR axis and switch to glycolysis. While differentiation of naive TRIM28−/−T cells into cytokine-producing effector T cells is impaired, resulting in reduced induction of autoimmune colitis, TRIM28−/−regulatory T cells also fail to expand in vivo and to suppress autoimmunity effectively. Using a combination of transcriptome and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses for H3K9me3, H3K9Ac, and RNA polymerase II, we show that reduced effector differentiation correlates with impaired transcriptional silencing at distal regulatory regions of a defined set of Treg-associated genes, including, for example, NRP1 or Snai3. We conclude that TRIM28 and HP1β/γ control metabolic reprograming through epigenetic silencing of a defined set of Treg-characteristic genes, thus allowing effective T cell expansion and differentiation into helper and regulatory phenotypes.
16
Fedoroff, Nina, Jo Ann Banks, and Patrick Masson. "Molecular genetic analysis of the maize Suppressor-mutator element's epigenetic developmental regulatory mechanism." Genome 31, no. 2 (January 15, 1989): 973–79. http://dx.doi.org/10.1139/g89-170.
Full textAbstract:
The genetic mechanism underlying the developmental regulation of the maize Suppressor-mutator element has been analyzed by molecular and genetic techniques. The element is subject to inactivation by a negative, epigenetic mechanism that results in the methylation of C residues in the vicinity of the element's transcription start site. Fully methylated elements are genetically and transcriptionally silent (cryptic), while hypomethylated elements are active. Partially methylated elements, designated programable, exhibit a variety of developmental expression programs. The element encodes a positive regulatory gene product which activates element expression and promotes reprograming of the element by interfering with methylation of the element's 5′ end.Key words: maize transposable element, Suppressor-mutator element, developmental regulation.
17
Arif, Stern, Pittala, Chalifa-Caspi, and Shoshan-Barmatz. "Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept." Cells 8, no. 11 (October 28, 2019): 1330. http://dx.doi.org/10.3390/cells8111330.
Full textAbstract:
Reprograming of the metabolism of cancer cells is an event recognized as a hallmark of the disease. The mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1), mediates transport of metabolites and ions in and out of mitochondria, and is involved in mitochondria-mediated apoptosis. Here, we compared the effects of reducing hVDAC1 expression in a glioblastoma xenograft using human-specific si-RNA (si-hVDAC1) for a short (19 days) and a long term (40 days). Tumors underwent reprograming, reflected in rewired metabolism, eradication of cancer stem cells (CSCs) and differentiation. Short- and long-term treatments of the tumors with si-hVDAC1 similarly reduced the expression of metabolism-related enzymes, and translocator protein (TSPO) and CSCs markers. In contrast, differentiation into cells expressing astrocyte or neuronal markers was noted only after a long period during which the tumor cells were hVDAC1-depleted. This suggests that tumor cell differentiation is a prolonged process that precedes metabolic reprograming and the “disappearance” of CSCs. Tumor proteomics analysis revealing global changes in the expression levels of proteins associated with signaling, synthesis and degradation of proteins, DNA structure and replication and epigenetic changes, all of which were highly altered after a long period of si-hVDAC1 tumor treatment. The depletion of hVDAC1 greatly reduced the levels of the multifunctional translocator protein TSPO, which is overexpressed in both the mitochondria and the nucleus of the tumor. The results thus show that VDAC1 depletion-mediated cancer cell metabolic reprograming involves a chain of events occurring in a sequential manner leading to a reversal of the unique properties of the tumor, indicative of the interplay between metabolism and oncogenic signaling networks.
18
Ahmad, Aamir. "Corruptive Reprograming of Macrophages into Tumor-Associated Macrophages: The Transcriptional, Epigenetic and Metabolic Basis." Cancers 15, no. 17 (August 28, 2023): 4291. http://dx.doi.org/10.3390/cancers15174291.
Full text
19
Munger, Karl, and D. Leanne Jones. "Human Papillomavirus Carcinogenesis: an Identity Crisis in the Retinoblastoma Tumor Suppressor Pathway." Journal of Virology 89, no. 9 (February 11, 2015): 4708–11. http://dx.doi.org/10.1128/jvi.03486-14.
Full textAbstract:
Viruses are obligate intracellular parasites and need to reprogram host cells to establish long-term persistent infection and/or to produce viral progeny. Cellular changes initiated by the virus trigger cellular defense responses to cripple viral replication, and viruses have evolved countermeasures to neutralize them. Established models have suggested that human papillomaviruses target the retinoblastoma (RB1) and TP53 tumor suppressor networks to usurp cellular replication, which drives carcinogenesis. More recent studies, however, suggest that modulating the activity of the Polycomb family of transcriptional repressors and the resulting changes in epigenetic regulation are proximal steps in the rewiring of cellular signaling circuits. Consequently, RB1 inactivation evolved to tolerate the resulting cellular alterations. Therefore, epigenetic reprograming results in cellular “addictions” to pathways for survival. Inhibition of such a pathway could cause “synthetic lethality” in adapted cells while not markedly affecting normal cells and could prove to be an effective therapeutic approach.
20
Özbek, Rabia, Krishnendu Mukherjee, Fevzi Uçkan, and Andreas Vilcinskas. "Reprograming of epigenetic mechanisms controlling host insect immunity and development in response to egg-laying by a parasitoid wasp." Proceedings of the Royal Society B: Biological Sciences 287, no. 1928 (June 10, 2020): 20200704. http://dx.doi.org/10.1098/rspb.2020.0704.
Full textAbstract:
Parasitoids are insects that use other insects as hosts. They sabotage host cellular and humoral defences to promote the survival of their offspring by injecting viruses and venoms along with their eggs. Many pathogens and parasites disrupt host epigenetic mechanisms to overcome immune system defences, and we hypothesized that parasitoids may use the same strategy. We used the ichneumon wasp Pimpla turionellae as a model idiobiont parasitoid to test this hypothesis, with pupae of the greater wax moth Galleria mellonella as the host. We found that parasitoid infestation involves the suppression of host immunity-related effector genes and the modulation of host genes involved in developmental hormone signalling. The transcriptional reprogramming of host genes following the injection of parasitoid eggs was associated with changes in host epigenetic mechanisms. The introduction of parasitoids resulted in a transient decrease in host global DNA methylation and the modulation of acetylation ratios for specific histones. Genes encoding regulators of histone acetylation and deacetylation were mostly downregulated in the parasitized pupae, suggesting that parasitoids can suppress host transcription. We also detected a strong parasitoid-specific effect on host microRNAs regulating gene expression at the post-transcriptional level. Our data therefore support the hypothesis that parasitoids may favour the survival of their offspring by interfering with host epigenetic mechanisms to suppress the immune system and disrupt development.
21
Corrêa, Régis L., Alejandro Sanz-Carbonell, Zala Kogej, Sebastian Y. Müller, Silvia Ambrós, Sara López-Gomollón, Gustavo Gómez, David C. Baulcombe, and Santiago F. Elena. "Viral Fitness Determines the Magnitude of Transcriptomic and Epigenomic Reprograming of Defense Responses in Plants." Molecular Biology and Evolution 37, no. 7 (April 7, 2020): 1866–81. http://dx.doi.org/10.1093/molbev/msaa091.
Full textAbstract:
Abstract Although epigenetic factors may influence the expression of defense genes in plants, their role in antiviral responses and the impact of viral adaptation and evolution in shaping these interactions are still poorly explored. We used two isolates of turnip mosaic potyvirus with varying degrees of adaptation to Arabidopsis thaliana to address these issues. One of the isolates was experimentally evolved in the plant and presented increased load and virulence relative to the ancestral isolate. The magnitude of the transcriptomic responses was larger for the evolved isolate and indicated a role of innate immunity systems triggered by molecular patterns and effectors in the infection process. Several transposable elements located in different chromatin contexts and epigenetic-related genes were also affected. Correspondingly, mutant plants having loss or gain of repressive marks were, respectively, more tolerant and susceptible to turnip mosaic potyvirus, with a more efficient response against the ancestral isolate. In wild-type plants, both isolates induced similar levels of cytosine methylation changes, including in and around transposable elements and stress-related genes. Results collectively suggested that apart from RNA silencing and basal immunity systems, DNA methylation and histone modification pathways may also be required for mounting proper antiviral defenses and that the effectiveness of this type of regulation strongly depends on the degree of viral adaptation to the host.
22
Day, Charles, Alyssa Langfald, Florina Grigore, Sela Fadness, Leslie Sepaniac, Jason Stumpff, Kevin Vaughan, James Robinson, and Edward Hinchcliffe. "DIPG-05. HISTONE H3.3 K27M IMPAIRS SER31 PHOSPHORYLATION, RESULTING IN CHROMOSOMAL INSTABILITY, LOSS OF CELL CYCLE CHECKPOINT CONTROL, AND TUMOR FORMATION." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii288. http://dx.doi.org/10.1093/neuonc/noaa222.057.
Full textAbstract:
Abstract Diffuse midline gliomas with the H3.3 K27M mutation are lethal brain tumors in children. H3 K27M causes global loss of Lys27 triple methylation (Lys27me3), inducing epigenetic reprograming. Here we show that H3.3 K27M also causes decreased H3.3 Ser31 phosphorylation on mitotic chromosomes. We show that H3.3 K27M DIPG cells have reduced pericentromeric phospho-Ser31 and increased rates of chromosome missegregation compared to normal, diploid human cells. CRISPR-editing K27M to M27K restored phospho-Ser31 to WT levels and dramatically decreased the rate of chromosome missegregation. We confirm that Chk1 is the H3.3 Ser31 kinase: K27M mutant H3.3 protein exhibits ~60% reduced Chk1 phosphorylation of Ser31 in vitro. Chk1 knockdown completely abolishes phospho-Ser31 in cells and these have increased rates of chromosome missegregation. In normal, diploid cells, expression of K27M or an S31A non-phosphorylatable mutant increased chromosome missegregation; this is suppressed by expressing a phosphomimetic double mutant (K27M/S31E) that restores phospho-Ser31. WT cells arrest following chromosome missegregation. However, cells expressing H3.3 K27M or S31A fail to arrest - despite having WT p53. Finally, we expressed H3F3AS31A and PDGFb in an RCAS/TVA mouse model of DIPG and ~80% developed diffuse high-grade brain tumors and show significantly decreased survival. Our results suggest that loss of phospho-Ser31 alone is oncogenic because H3.3 S31A-expressing cells are WT for K27me3. Our results demonstrate that H3.3 K27M inhibits Ser31 phosphorylation both in vitro and in vivo, leading to both chromosome missegregation and loss of subsequent G1 arrest – thus creating diffuse midline gliomas with both dynamic, complex karyotypes and epigenetic reprogramming.
23
Kutschat, Ana P., Steven A. Johnsen, and Feda H. Hamdan. "Store-Operated Calcium Entry: Shaping the Transcriptional and Epigenetic Landscape in Pancreatic Cancer." Cells 10, no. 5 (April 21, 2021): 966. http://dx.doi.org/10.3390/cells10050966.
Full textAbstract:
Pancreatic ductal adenocarcinoma (PDAC) displays a particularly poor prognosis and low survival rate, mainly due to late diagnosis and high incidence of chemotherapy resistance. Genomic aberrations, together with changes in the epigenomic profile, elicit a shift in cellular signaling response and a transcriptional reprograming in pancreatic tumors. This endows them with malignant attributes that enable them to not only overcome chemotherapeutic challenges, but to also attain diverse oncogenic properties. In fact, certain genetic amplifications elicit a rewiring of calcium signaling, which can confer ER stress resistance to tumors while also aberrantly activating known drivers of oncogenic programs such as NFAT. While calcium is a well-known second messenger, the transcriptional programs driven by aberrant calcium signaling remain largely undescribed in pancreatic cancer. In this review, we focus on calcium-dependent signaling and its role in epigenetic programs and transcriptional regulation. We also briefly discuss genetic aberration events, exemplifying how genetic alterations can rewire cellular signaling cascades, including calcium-dependent ones.
24
Sato, Hiromichi, Tomoaki Hara, Sikun Meng, Yoshiko Tsuji, Yasuko Arao, Kazuki Sasaki, Norikatsu Miyoshi, et al. "Drug Discovery and Development of miRNA-Based Nucleotide Drugs for Gastrointestinal Cancer." Biomedicines 11, no. 8 (August 9, 2023): 2235. http://dx.doi.org/10.3390/biomedicines11082235.
Full textAbstract:
Short non-coding RNAs, miRNAs, play roles in the control of cell growth and differentiation in cancer. Reportedly, the introduction of miRNAs could reduce the biologically malignant behavior of cancer cells, suggesting a possible use as therapeutic reagents. Given that the forced expression of several miRNAs, including miR-302, results in the cellular reprograming of human and mouse cells, which is similar to the effects of the transcription factors Oct4, Sox2, Klf4, and c-Myc, this suggests that the selective introduction of several miRNAs will be able to achieve anti-cancer effects at the epigenetic and metabolic levels. In this review article, we bring together the recent advances made in studies of microRNA-based therapeutic approaches to therapy-resistant cancers, especially in gastrointestinal organs.
25
Tanaka, Atsushi. "How to Improve Clinical Outcome in ROSI." Fertility & Reproduction 05, no. 04 (December 2023): 275. http://dx.doi.org/10.1142/s2661318223740894.
Full textAbstract:
In 1996, Tesarik reported the first successful case of ROSI and many successful cases were reported around the world, however very few cases of deliveries were reported. Many doctors began to become doubtful about the usefulness of ROSI and it almost disappeared from the field of ART. Based on recent advances on ROSI research, I think it is now necessary to reconsider the usefulness of ROSI. There are three issues concerning the extremely low success rate of ROSI. The first is the cytodifferentiation of round spermatid from other round cells. The most difficult cytological differentiation is between spermatogonia and round spermatid. The second is insufficient oocyte activation. Finally, ROSI improvement is being prevented by epigenetic errors. The big difference in ROSI and ICSI is caused by different nuclear proteins. We are now experimenting how to solve those epigenetic errors using histone deacetylase inhibitor. The first two problems have almost been solved. The only problem we are yet to overcome is the epigenetic abnormality. The big difference between ROSI and ICSI is the different type of nuclear protein. In a round spermatid is histone and in a spermatozoon is protamine. Normal transformation of nucleosomes into nucleoprotamine is generated in normal spermatogenesis. The characteristics of nuclei of RS are ①incomplete histone-protein transition (incomplete chromatin reprograming), ②active DNA demethylation, then these epigenetic errors affect gene expression. We are now conducting some experiments to solve these problems. The experiment involves the correction of abnormal gene expression by using histone deacetylase inhibitor. However, this method is not yet allowed clinically. I believe these procedures will be allowed for clinical application after accumulation of positive evidence by researchers.
26
Goto, Norihiro, Saori Goto, Peter Westcott, Shinya Imada, Judith Agudo, and Omer Yilmaz. "Abstract 1352: SOX17 plays a critical role in immune evasion of colorectal cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1352. http://dx.doi.org/10.1158/1538-7445.am2023-1352.
Full textAbstract:
Abstract Colorectal cancers (CRCs) are a leading cause of cancer-related death. Most CRCs are immune cold, and do not respond to checkpoint blockade therapy except for microsatellite-high CRCs harboring high mutational burdens. Deciphering the mechanism by which CRC cells evade immune surveillance has the potential to dramatically improve the prognosis of CRC patients. During tumor evolution of CRCs, epigenetic changes play critical roles in addition to accumulation of genetic mutations. However, distinct mutational patterns and patient backgrounds render it challenging to distinguish the driver epigenetic alterations from passenger epigenetic alterations induced by gene mutations or other environmental factors. Identification of the driver epigenetic alterations may provide novel mechanistic insights into colon cancer biology including how they evade immune surveillance. Here, we utilized the colon cancer organoid orthotopic transplantation approach to establish colon cancer organoids from different stages of the tumors, and performed comprehensive epigenomic and transcriptomic analyses to understand the epigenetic alterations during tumor evolution. We found that in vivo environment induces epigenetic alterations that converge on SOX17, a transcription factor that is required for endoderm development. SOX17 is re-expressed in colon cancers in vivo, but not in the in vitro organoid culture, and reprograms tumor cell fate with fetal intestinal gene expressions. Importantly, SOX17 knockout leads to tumor rejection in immunocompetent mice, but not in immunodeficient mice, by turning immune cold tumors into hot tumors with robust intratumoral infiltration of activated CD8+ T cells. Mechanistically, SOX17 directly downregulates Ifngr1 expression and mitigates MHC-I expression to evade CD8+ T cell-mediated tumor cell killing. Together, our result reveals that SOX17 is a master transcription factor that induces the in vivo epigenetic reprograming of tumors, which contributes to the immune evasion of colon cancers. Citation Format: Norihiro Goto, Saori Goto, Peter Westcott, Shinya Imada, Judith Agudo, Omer Yilmaz. SOX17 plays a critical role in immune evasion of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1352.
27
Renatino-Canevarolo, Rafael, Mark B. Meads, Maria Silva, Praneeth Reddy Sudalagunta, Christopher Cubitt, Gabriel De Avila, Raghunandan R. Alugubelli, et al. "Dynamic Epigenetic Landscapes Define Multiple Myeloma Progression and Drug Resistance." Blood 136, Supplement 1 (November 5, 2020): 32–33. http://dx.doi.org/10.1182/blood-2020-142872.
Full textAbstract:
Multiple myeloma (MM) is an incurable cancer of bone marrow-resident plasma cells, which evolves from a premalignant state, MGUS, to a form of active disease characterized by an initial response to therapy, followed by cycles of therapeutic successes and failures, culminating in a fatal multi-drug resistant cancer. The molecular mechanisms leading to disease progression and refractory disease in MM remain poorly understood. To address this question, we have generated a new database, consisting of 1,123 MM biopsies from patients treated at the H. Lee Moffitt Cancer Center. These samples ranged from MGUS to late relapsed/refractory (LR) disease, and were comprehensively characterized genetically (844 RNAseq, 870 WES, 7 scRNAseq), epigenetically (10 single-cell chromatin accessibility, scATAC-seq) and phenotypically (537 samples assessed for ex vivo drug resistance). Mutational analysis identified putative driver genes (e.g. NRAS, KRAS) among the highest frequent mutations, as well as a steady increase in mutational load across progression from MGUS to LR samples. However, with the exception of KRAS, these genes did not reach statistical significance according to FISHER's exact test between different disease stages, suggesting that no single mutation is necessary or sufficient to drive MM progression or refractory disease, but rather a common "driver" biology is critical. Pathway analysis of differentially expressed genes identified cell adhesion, inflammatory cytokines and hematopoietic cell identify as under-expressed in active MM vs. MGUS, while cell cycle, metabolism, DNA repair, protein/RNA synthesis and degradation were over-expressed in LR. Using an unsupervised systems biology approach, we reconstructed a gene expression map to identify transcriptomic reprogramming events associated with disease progression and evolution of drug resistance. At an epigenetic regulatory level, these genes were enriched for histone modifications (e.g. H3k27me3 and H3k27ac). Furthermore, scATAC-seq confirmed genome-wide alterations in chromatin accessibility across MM progression, involving shifts in chromatin accessibility of the binding motifs of epigenetic regulator complexes, known to mediate formation of 3D structures (CTCF/YY1) of super enhancers (SE) and cell identity reprograming (POU5F1/SOX2). Additionally, we have identified SE-regulated genes under- (EBF1, RB1, SPI1, KLF6) and over-expressed (PRDM1, IRF4) in MM progression, as well as over-expressed in LR (RFX5, YY1, NBN, CTCF, BCOR). We have found a correlation between cytogenetic abnormalities and mutations with differential gene expression observed in MM progression, suggesting groups of genetic events with equivalent transcriptomic effect: e.g. NRAS, KRAS, DIS3 and del13q are associated with transcriptomic changes observed during MGUS/SMOL=>active MM transition (Figure 1). Taken together, our preliminary data suggests that multiple independent combinations of genetic and epigenetic events (e.g. mutations, cytogenetics, SE dysregulation) alter the balance of master epigenetic regulatory circuitry, leading to genome-wide transcriptional reprogramming, facilitating disease progression and emergence of drug resistance. Figure 1: Topology of transcriptional regulation in MM depicts 16,738 genes whose expression is increased (red) or decreased (green) in presence of genetic abnormality. Differential expression associated with (A) hotspot mutations and (B) cytogenetic abnormalities confirms equivalence of expected pairs (e.g. NRAS and KRAS, BRAF and RAF1), but also proposes novel transcriptomic dysregulation effect of clinically relevant cytogenetic abnormalities, with yet uncharacterized molecular role in MM. Figure 1 Disclosures Kulkarni: M2GEN: Current Employment. Zhang:M2GEN: Current Employment. Hampton:M2GEN: Current Employment. Shain:GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; AbbVie: Research Funding; Takeda: Honoraria, Speakers Bureau; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive: Consultancy, Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Siqueira Silva:AbbVie: Research Funding; Karyopharm: Research Funding; NIH/NCI: Research Funding.
28
Velasquez-Vasconez, Pedro A., Benjamin J. Hunt, Renata O. Dias, Thaís P. Souza, Chris Bass, and Marcio C. Silva-Filho. "Adaptation of Helicoverpa armigera to Soybean Peptidase Inhibitors Is Associated with the Transgenerational Upregulation of Serine Peptidases." International Journal of Molecular Sciences 23, no. 22 (November 18, 2022): 14301. http://dx.doi.org/10.3390/ijms232214301.
Full textAbstract:
Molecular phenotypes induced by environmental stimuli can be transmitted to offspring through epigenetic inheritance. Using transcriptome profiling, we show that the adaptation of Helicoverpa armigera larvae to soybean peptidase inhibitors (SPIs) is associated with large-scale gene expression changes including the upregulation of genes encoding serine peptidases in the digestive system. Furthermore, approximately 60% of the gene expression changes induced by SPIs persisted in the next generation of larvae fed on SPI-free diets including genes encoding regulatory, oxidoreductase, and protease functions. To investigate the role of epigenetic mechanisms in regulating SPI adaptation, the methylome of the digestive system of first-generation larvae (fed on a diet with and without SPIs) and of the progeny of larvae exposed to SPIs were characterized. A comparative analysis between RNA-seq and Methyl-seq data did not show a direct relationship between differentially methylated and differentially expressed genes, while trypsin and chymotrypsin genes were unmethylated in all treatments. Rather, DNA methylation potential epialleles were associated with transcriptional and translational controls; these may play a regulatory role in the adaptation of H. armigera to SPIs. Altogether, our findings provided insight into the mechanisms of insect adaptation to plant antiherbivore defense proteins and illustrated how large-scale transcriptional reprograming of insect genes can be transmitted across generations.
29
Wang, Zhishan, and Chengfeng Yang. "Metal carcinogen exposure induces cancer stem cell-like property through epigenetic reprograming: A novel mechanism of metal carcinogenesis." Seminars in Cancer Biology 57 (August 2019): 95–104. http://dx.doi.org/10.1016/j.semcancer.2019.01.002.
Full text
30
Ma, Xuan, Feng Xing, Qingxiao Jia, Qinglu Zhang, Tong Hu, Baoguo Wu, Lin Shao, Yu Zhao, Qifa Zhang, and Dao-Xiu Zhou. "Parental variation in CHG methylation is associated with allelic-specific expression in elite hybrid rice." Plant Physiology 186, no. 2 (February 23, 2021): 1025–41. http://dx.doi.org/10.1093/plphys/kiab088.
Full textAbstract:
Abstract Heterosis refers to the superior performance of hybrid lines over inbred parental lines. Besides genetic variation, epigenetic differences between parental lines are suggested to contribute to heterosis. However, the precise nature and extent of differences between the parental epigenomes and the reprograming in hybrids that govern heterotic gene expression remain unclear. In this work, we analyzed DNA methylomes and transcriptomes of the widely cultivated and genetically studied elite hybrid rice (Oryza sativa) SY63, the reciprocal hybrid, and the parental varieties ZS97 and MH63, for which high-quality reference genomic sequences are available. We showed that the parental varieties displayed substantial variation in genic methylation at CG and CHG (H = A, C, or T) sequences. Compared with their parents, the hybrids displayed dynamic methylation variation during development. However, many parental differentially methylated regions (DMRs) at CG and CHG sites were maintained in the hybrid. Only a small fraction of the DMRs displayed non-additive DNA methylation variation, which, however, showed no overall correlation relationship with gene expression variation. In contrast, most of the allelic-specific expression (ASE) genes in the hybrid were associated with DNA methylation, and the ASE negatively associated with allelic-specific methylation (ASM) at CHG. These results revealed a specific DNA methylation reprogramming pattern in the hybrid rice and pointed to a role for parental CHG methylation divergence in ASE, which is associated with phenotype variation and hybrid vigor in several plant species.
31
Koul, Hari K., Mousa Vatanmakanian, Ellen Nogueira Lima, Lakshmi S. Chaturvedi, and Sweaty K. Koul. "DNA methyl-transferases (DNMTs) as potential therapeutic vulnerability in prostate cancer." Journal of Clinical Oncology 42, no. 4_suppl (February 1, 2024): 339. http://dx.doi.org/10.1200/jco.2024.42.4_suppl.339.
Full textAbstract:
339 Background: Prostate cancer (PCa) presents a significant health challenge in men, with a substantial number of deaths attributed to resistance to current Androgen Receptor inhibitors, and emergence of CRPC-adeno, CRPC-NEPC and CRPC-DNPC phenotypes. There is an urgent and unmet need for developing new targets for CRPC especially CRPC-NEPC and CRPC-DNPC. Because cellular plasticity plays a central role in transition to NEPC and DNPC, molecular targets that are critical for prostate cancer cellular plasticity could serve as actionable targets in therapy resistance in prostate cancer. In this study we explored potential role of DNA methyl-transferases in prostate cancer therapy resistance. Methods: We analyzed publicly available clinical datasets to investigate expression of DNMTs (DNMT1, DNMT3a, and DNMT3b), and the association between expression of DNMTs, and prostate cancer progression, neuroendocrine features and overall survival. We evaluated effects of DNMT inhibitor [5-aza-2′-deoxycytidine (5AdC)] in short term experiments PCa cell lines to measure cell viability. We performed epigenetic reprograming by culturing PCa cells in sublethal doses of 5AdC over long term and measured cell migration and invasion. Results: Expression of DNMTs (DNMT1, 3a and 3b) is increased during prostate cancer progression, and there is a positive correlation between DNMT (DNMT1, DNMT3a, and DNMT3b) expression and tumor progression (increasing Gleason score) and NEPC score, and a negative correlation between DNMT expression and patient survival. DNMT1, DNMT3a and DNMT3b are expressed in androgen dependent as well as CRPC cell lines. All PCa cell lines were sensitive to DNMT inhibition (5AdC treatment). 5AdC was as effective as enzalutamide in limiting cell growth and proliferation in enzalutamide sensitive LNCaP cells, and sensitized these cells to enzalutamide. Moreover, 5AdC treatment also halted growth and proliferation of CRPC cell lines (PC3 and DU145) and epigenetic reprograming of these cells with 5AdC decreased cell migration and invasion. Conclusions: These results indicate DNMT expression is associated with prostate cancer progression. These studies suggest DMNT activity as a potential therapeutic vulnerability that can be exploited for limiting cellular plasticity, tumor progression, and therapy resistance in prostate cancer. Because DNMT inhibitors are currently approved for other malignancies, addition of these inhibitors to current treatment regiments could be readily explored in PCa.
32
Bitman-Lotan, Eliya, and Amir Orian. "Nuclear organization and regulation of the differentiated state." Cellular and Molecular Life Sciences 78, no. 7 (January 28, 2021): 3141–58. http://dx.doi.org/10.1007/s00018-020-03731-4.
Full textAbstract:
AbstractRegulation of the differentiated identity requires active and continued supervision. Inability to maintain the differentiated state is a hallmark of aging and aging-related disease. To maintain cellular identity, a network of nuclear regulators is devoted to silencing previous and non-relevant gene programs. This network involves transcription factors, epigenetic regulators, and the localization of silent genes to heterochromatin. Together, identity supervisors mold and maintain the unique nuclear environment of the differentiated cell. This review describes recent discoveries regarding mechanisms and regulators that supervise the differentiated identity and protect from de-differentiation, tumorigenesis, and attenuate forced somatic cell reprograming. The review focuses on mechanisms involved in H3K9me3-decorated heterochromatin and the importance of nuclear lamins in cell identity. We outline how the biophysical properties of these factors are involved in self-compartmentalization of heterochromatin and cell identity. Finally, we discuss the relevance of these regulators to aging and age-related disease.
33
Jaune-Pons, Emilie, Zachary Klassen, Rachel Lu, Ye Shen, Nadeem Hussain, Michael Sey, Ken Leslie, et al. "Abstract B067: Patient-specific differences in cancer-associated fibroblasts alter tumor organoid phenotype and chemosensitivity in pancreatic ductal adenocarcinoma." Cancer Research 84, no. 2_Supplement (January 16, 2024): B067. http://dx.doi.org/10.1158/1538-7445.panca2023-b067.
Full textAbstract:
Abstract Pancreatic adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related deaths in Canada with a 5-year survival rate ~10%. Unfortunately, only 20% of patients are eligible for surgical resection while the other 80% of patients are treated with chemotherapy (i.e. nab-paclitaxel, Gemcitabine, or FOLFIRINOX) that shows limited efficiency. Also, the tumor microenvironment (TME), and specifically cancer-associated fibroblasts (CAFs), contribute to PDAC chemoresistance. Recent studies suggest heterogeneity of CAF subtypes in patients, including myofibroblast (my), inflammatory (i), and antigen-presenting (ap) CAFs, is linked to more aggressive PDAC. While there is clear evidence CAFs effect tumor growth, chemoresistance and metastasis, the mechanisms underlying these effects are unknown. Given the involvement of environmental cues from the TME and the recent literature involving HDACs and epigenetic regulators in chemoresistance, we propose epigenetic reprogramming occurs in pancreatic cancer cells in response to CAFs, thereby affecting their response to chemotherapy. Using patient-derived tumor cells we examine the cross talk that occurs between cancer cells and CAFs in a patient-specific manner. We hypothesized that patient-specific CAF populations alter cancer cell phenotypes and chemosensitivity through epigenetic reprograming. Supported by the Baker Centre for Pancreatic Cancer, we established a living biobank of patient-derived organoids (PDO) grown in 3D cultures and CAFs grown in 2D cultures. These samples are linked to DERIVE (Determination of Response to Therapy in Individual Patients), a clinical database that includes patient response to therapy. Characterization of low passage, patient CAFs by flow cytometry shows significant heterogeneity between samples based on the proportions of myCAFs, iCAFs and apCAFs, and also identified CAFs that do not belong to any of these subtypes. Incubation of PDOs with CAF-conditioned media showed an increase in growth regardless of the CAF samples but, interestingly, myCAF-high (myCAFHI) conditioned media promoted a cystic-like phenotype in PDOs while iCAF-high conditioned media promoted a more complex PDO phenotype. myCAFHI-conditioned media also sensitized resistant PDOs to gemcitabine. Characterization of epigenetic mediators showed variable expression of histone deacetylases (HDACs), and combinatorial treatment with gemcitabine and the HDAC5 inhibitor, LMK-235 sensitized resistant PDOs to gemcitabine. We are currently performing single-cell RNA-seq, ATAC-seq and DNA methylation profiling on PDOs before and after treatment with CAF-conditioned media to identify unique CAF populations and examine the epigenetic targets underlying these outcomes. This study (1) shows CAFs present with significant heterogeneity between patients and secreted factors from CAFs induce responses in a patient-specific fashion that may change chemosensitivity, and (2) suggest targeting epigenetic mediators in PDOs and CAFs may help sensitize tumors to chemotherapy. Citation Format: Emilie Jaune-Pons, Zachary Klassen, Rachel Lu, Ye Shen, Nadeem Hussain, Michael Sey, Ken Leslie, Ephraim Tang, Anton Skaro, Matthew Cecchini, Crystal Engelage, Danielle Porplycia, Stephen Welch, Brian Yan, Christopher Pin. Patient-specific differences in cancer-associated fibroblasts alter tumor organoid phenotype and chemosensitivity in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B067.
34
Kelly, Rebeca, Diego Aviles, David Philip Warshal, Lauren Krill, and Olga Ostrovsky. "Can epigenetic treatments efficiently revoke the ability of 3D ovarian cancer cells to proliferate, migrate, and invade?" Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e17562-e17562. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e17562.
Full textAbstract:
e17562 Background: 3D ovarian cancer propagation and metastasis arise not only from genetic mutations, but from aberrant epigenetic modifications known to involve mechanisms of DNA methylation and histone deacetylation. Clinically, cancer induces epigenetic aberrations in adipose-derived stem cells from omentum (O-ASCs), creating a tumorigenic microenvironment that supports chemoresistance and dissemination of disease. Epigallocatechin gallate (EGCG), a DNA methyltransferase inhibitor derived from green tea, and Indole-3-carbinol (I3C), a histone deacetylase inhibitor from cruciferous vegetables, carry promising effects in reprograming aberrant epigenetic modifications in cancer. Therefore, we investigate whether these diet-derived compounds can suppress proliferation, migration and invasion of ovarian cancer in 3D-spheroids or 3D-organoids with O-ASCs when compared to synthetic Panobinostat (Pano) and cisplatin/paclitaxol (C/T). Methods: 3D ovarian cancer spheroids and organoids (30% O-ASCs) were treated with EGCG (10, 50 µm), I3C (50, 200 µm), Pano (5, 15 µm) and C/T. Percent growth was followed for 17 days and compared to an untreated control group. Post-treated cancer was then derived from 3D structures and tested for its ability to regrow (MTT assay), to form colonies (CFU), and to migrate and invade (CytoSelect Cell Migration and Invasion assay). Results: Our results show that higher doses of epigenetic regimens more efficiently suppress growth of 3D ovarian cancer when compared to the control and C/T groups (p<.05). Additionally, the synthetic epigenetic drug Pano also efficiently suppressed cancer as compared to control and C/T treated cells (p<.05). Given that experimental treatments efficiently down-regulated 3D cancer growth, follow up of post-treatment cancer recovery was analyzed through multiple biochemical and biological assays. 3D derived cells pre-treated with EGCG, I3C and Pano had significant lower proliferation capacity as compared to control or C/T as demonstrated by an MTT assay (p<.05). While all epigenetic treatments inhibited CFU in the spheroid derived group, EGCG was not able to fully inhibit CFU in the organoid group. Further, inhibition of CFU was not noted in the C/T pre-treated cells. Finally, the ability of cells to migrate and invade following treatment was more efficiently suppressed in cells derived from organoids. I3C and Pano significantly suppressed cancer migration, while EGCG and Pano suppressed invasion (p<.05). Conclusions: Diet-derived epigenetic treatments can reprogram epigenetic aberrations involved in mechanisms of proliferation, migration and invasion of 3D ovarian cancer. Our results suggest that these treatments not only suppress 3D cancer growth and post-treatment regrowth, but could be considered as adjuncts to standard chemotherapy, improving efficiency and patient outcomes.
35
Funk, Christopher Ronald, Shuhua Wang, Kevin Z. Chen, Alexandra Waller, Aditi Sharma, Claudia L. Edgar, Vikas A. Gupta, et al. "PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity." Blood 139, no. 4 (January 27, 2022): 523–37. http://dx.doi.org/10.1182/blood.2021011597.
Full textAbstract:
Abstract Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhausted phenotype and experience low complete response rates after autologous CART therapy. Because PI3K inhibitor therapy is associated with the development of T-cell–mediated autoimmunity, we studied the effects of inhibiting the PI3Kδ and PI3Kγ isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3Kδ/γ inhibition normalized CD4/CD8 ratios and maximized the number of CD8+ T-stem cell memory, naive, and central memory T-cells with dose-dependent decreases in expression of the TIM-3 exhaustion marker. CART cells manufactured with duvelisib (Duv-CART cells) showed significantly increased in vitro cytotoxicity against CD19+ CLL targets caused by increased frequencies of CD8+ CART cells. Duv-CART cells had increased expression of the mitochondrial fusion protein MFN2, with an associated increase in the relative content of mitochondria. Duv-CART cells exhibited increased SIRT1 and TCF1/7 expression, which correlated with epigenetic reprograming of Duv-CART cells toward stem-like properties. After transfer to NOG mice engrafted with a human CLL cell line, Duv-CART cells expressing either a CD28 or 41BB costimulatory domain demonstrated significantly increased in vivo expansion of CD8+ CART cells, faster elimination of CLL, and longer persistence. Duv-CART cells significantly enhanced survival of CLL-bearing mice compared with conventionally manufactured CART cells. In summary, exposure of CART to a PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo.
36
Huang, Xin, Xudong Gao, Wanying Li, Shuai Jiang, Ruijiang Li, Hao Hong, Chenghui Zhao, et al. "Stable H3K4me3 is associated with transcription initiation during early embryo development." Bioinformatics 35, no. 20 (March 12, 2019): 3931–36. http://dx.doi.org/10.1093/bioinformatics/btz173.
Full textAbstract:
Abstract Motivation During development of the mammalian embryo, histone modification H3K4me3 plays an important role in regulating gene expression and exhibits extensive reprograming on the parental genomes. In addition to these dramatic epigenetic changes, certain unchanging regulatory elements are also essential for embryonic development. Results Using large-scale H3K4me3 chromatin immunoprecipitation sequencing data, we identified a form of H3K4me3 that was present during all eight stages of the mouse embryo before implantation. This ‘stable H3K4me3’ was highly accessible and much longer than normal H3K4me3. Moreover, most of the stable H3K4me3 was in the promoter region and was enriched in higher chromatin architecture. Using in-depth analysis, we demonstrated that stable H3K4me3 was related to higher gene expression levels and transcriptional initiation during embryonic development. Furthermore, stable H3K4me3 was much more active in blood tumor cells than in normal blood cells, suggesting a potential mechanism of cancer progression. Supplementary information Supplementary data are available at Bioinformatics online.
37
Sobolewski, Marissa, Garima Varma, Beth Adams, David W. Anderson, Jay S. Schneider, and Deborah A. Cory-Slechta. "Developmental Lead Exposure and Prenatal Stress Result in Sex-Specific Reprograming of Adult Stress Physiology and Epigenetic Profiles in Brain." Toxicological Sciences 163, no. 2 (February 21, 2018): 478–89. http://dx.doi.org/10.1093/toxsci/kfy046.
Full text
38
Chen, Longmin, Jing Zhang, Yuan Zou, Faxi Wang, Jingyi Li, Fei Sun, Xi Luo, et al. "Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus." Cell Death & Differentiation 28, no. 6 (January 18, 2021): 1880–99. http://dx.doi.org/10.1038/s41418-020-00714-7.
Full textAbstract:
AbstractKdm2a catalyzes H3K36me2 demethylation to play an intriguing epigenetic regulatory role in cell proliferation, differentiation, and apoptosis. Herein we found that myeloid-specific knockout of Kdm2a (LysM-Cre-Kdm2af/f, Kdm2a−/−) promoted macrophage M2 program by reprograming metabolic homeostasis through enhancing fatty acid uptake and lipolysis. Kdm2a−/− increased H3K36me2 levels at the Pparg locus along with augmented chromatin accessibility and Stat6 recruitment, which rendered macrophages with preferential M2 polarization. Therefore, the Kdm2a−/− mice were highly protected from high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis, and featured by the reduced accumulation of adipose tissue macrophages and repressed chronic inflammation following HFD challenge. Particularly, Kdm2a−/− macrophages provided a microenvironment in favor of thermogenesis. Upon HFD or cold challenge, the Kdm2a−/− mice manifested higher capacity for inducing adipose browning and beiging to promote energy expenditure. Collectively, our findings demonstrate the importance of Kdm2a-mediated H3K36 demethylation in orchestrating macrophage polarization, providing novel insight that targeting Kdm2a in macrophages could be a viable therapeutic approach against obesity and insulin resistance.
39
Eid, Wassim, and Wafaa Abdel-Rehim. "Vitamin C promotes pluripotency of human induced pluripotent stem cells via the histone demethylase JARID1A." Biological Chemistry 397, no. 11 (November 1, 2016): 1205–13. http://dx.doi.org/10.1515/hsz-2016-0181.
Full textAbstract:
Abstract Somatic cells can be reprogramed into induced pluripotent stem (iPS) cells by defined factors, which provide a powerful basis for personalized stem-cell based therapies. However, cellular reprograming is an inefficient and metabolically demanding process commonly associated with obstacles that hamper further use of this technology. Spontaneous differentiation of iPS cells cultures represents a significant hurdle that hinder obtaining high quality iPS cells for further downstream experimentation. In this study, we found that a natural compound, vitamin C, augmented pluripotency in iPS cells and reduced unwanted spontaneous differentiation during iPS cells maintenance. Gene expression analysis showed that vitamin C increased the expression of the histone demethylase JARID1A. Furthermore, through gain- and loss-of-function approaches, we show that JARID1A is a key effector in promoting pluripotency and reducing differentiation downstream of vitamin C. Our results therefore highlight a straightforward method for improving the pluripotency and quality of iPS cells; it also shows a possible role for H3K4me2/3 in cell fate determination and establishes a link between vitamin C and epigenetic regulation.
40
Stojanovic, Lora, Rachel Abbotts, Kaushlendra Tripathi, Collin M. Coon, Sheng Liu, Jun Wan, Michael J. Topper, Kenneth P. Nephew, Stephen B. Baylin, and Feyruz V. Rassool. "Abstract PR-005: ZNFX1 is a master regulator for epigenetic reprograming of mitochondrial inflammasome signaling and pathogen mimicry in cancer cells." Cancer Research 84, no. 5_Supplement_2 (March 4, 2024): PR—005—PR—005. http://dx.doi.org/10.1158/1538-7445.ovarian23-pr-005.
Full textAbstract:
Abstract Immunomodulatory agents represent an important recent advance in cancer therapy, but utility is often limited by tumor immune evasion mechanisms. Strategic therapeutic activation of intracellular antiviral immune responses offers an opportunity to reverse immune evasion mechanisms and improve treatment outcomes. Anti-cancer agents such as, DNA methyltransferase inhibitors (DNMTis) induce re-expression of endogenous retroviral elements (ERVs), leading to cytosolic double-stranded RNA (dsRNA) accumulation that activates interferon/inflammasome signaling. Moreover, poly (ADP ribose) polymerase inhibitors (PARPi) increase cytosolic dsDNA leading to activation of stimulator of interferon genes (STING). We previously reported in triple negative breast cancer (TNBC) and ovarian cancer (OC) that DNMTis in combination with PARPi induce STING-dependent interferon/inflammasome signaling in a process termed pathogen mimicry response (PMR). Mitochondria (mt) are an important gateway for antiviral inflammasome signaling, but upstream activating events in cancer are not understood. We now show NFX1-type zinc finger–containing 1 (ZNFX1), a little-studied innate immune gene, acts as a master nucleic acid (dsRNA/DNA) sensor for this mt gateway function. Importantly, in primary ovarian tumors from TCGA and clinical trial RNAseq datasets, increased ZNFX1 expression tracks with tumor stage and grade but inversely correlates with a mt dysfunction signature. In studies of high grade serous (TYK-nu, OVCAR4) as well as endometrial ovarian (A2780) cancer cells, transfection of dsRNA/DNA mimics or DNMTi azacytidine (AZA) and PARPi (talazoparib) treatments induce increased ZNFX1 expression and binding to mt antiviral protein (MAVs) localized on the mt outer membrane, using immunofluorescence-based proximity ligation assays. In studies of mt dysfunction, we further show that dsRNA/DNA as well as above-described anti-cancer drugs increase mt reactive oxygen species (ROS), using flow cytometry of ROS dye mitoSOX. DNMTi and PARPi treatments also increase fragmented mtDNA and oxidative mtDNA base damage, as measured long range PCR and 8-oxoguanine (8-oxoG) ELISA assays, respectively. Importantly, these drug treatment increase release of mtDNA into the cytosol, resulting in STING-dependent inflammasome signaling and cytokine release. ZNFX1 knockout robustly attenuates these dynamics, thus defining this immune gene as essential for interferon/inflammasome signaling induced by mtDNA damage. Our data indicates a master role for the little-studied dsRNA/DNA sensor ZNFX1 in initiating a pathogen mimicry response to DNMTi and PARPi combination treatment, and further highlights the critical role of the mt in cellular antiviral signaling mechanisms. Importantly, this work suggests a novel avenue for manipulation of inflammasome signaling to improve cancer therapy responses and disease outcomes. Citation Format: Lora Stojanovic, Rachel Abbotts, Kaushlendra Tripathi, Collin M. Coon, Sheng Liu, Jun Wan, Michael J. Topper, Kenneth P. Nephew, Stephen B. Baylin, Feyruz V. Rassool. ZNFX1 is a master regulator for epigenetic reprograming of mitochondrial inflammasome signaling and pathogen mimicry in cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr PR-005.
41
de Lima Camillo, Lucas Paulo, and Robert B. A. Quinlan. "A ride through the epigenetic landscape: aging reversal by reprogramming." GeroScience 43, no. 2 (April 2021): 463–85. http://dx.doi.org/10.1007/s11357-021-00358-6.
Full textAbstract:
AbstractAging has become one of the fastest-growing research topics in biology. However, exactly how the aging process occurs remains unknown. Epigenetics plays a significant role, and several epigenetic interventions can modulate lifespan. This review will explore the interplay between epigenetics and aging, and how epigenetic reprogramming can be harnessed for age reversal. In vivo partial reprogramming holds great promise as a possible therapy, but several limitations remain. Rejuvenation by reprogramming is a young but rapidly expanding subfield in the biology of aging.
42
Bae, Jooeun, Shuichi Kitayama, Zach Herbert, Laurence Daheron, Nikhil C. Munshi, Shin Kaneko, Jerome Ritz, and Kenneth Carl Anderson. "Development of B-cell maturation antigen (BCMA)-specific CD8+ cytotoxic T lymphocytes using induced pluripotent stem cell technology for multiple myeloma." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 2542. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2542.
Full textAbstract:
2542 Background: A strategy for reversal of T cell exhaustion is reprograming of antigen-specific CTL to early lineage memory T cells with selective anti-tumor activities. To accomplish this goal, we epigenetically reprogrammed BCMA-specific CD8+ CTL to a pluripotent state through key defined transcription factors, established “induced Pluripotent Stem Cells (iPSC)” exhibiting transcriptional and epigenetic features, re-differentiated them back into antigen-specific CTL and evaluated their properties and functional activities against multiple myeloma (MM). Methods: Functionally activeIFN-g producing HLA-A2 heteroclitic BCMA72-80 (YLMFLLRKI)-specific CD8+ CTL were applied for iPSC via transduction of four reprogramming factors (OCT3/4, SOX2, KLF4, c-MYC). Upon characterization of the BCMA-specific iPSC with high pluripotency potential, embryoid body was formed from the iPSC and further polarized into mesoderm layer development as evidenced by upregulation of transcriptional regulators (ABCA4, BMP10, CDH5, FOXF1, HAND1, PLVAP, SNAI2, TBX3). Next, BCMA-specific embryoid body-derived hematopoietic progenitor cells (HPC; CD34+ CD43+/CD14- CD235a-) were sorted and induced to undergo T cell differentiation in the presence of Fc-DLL4 signaling and rectonectin. Results: Our RNAseq analyses demonstrated unique transcriptional profiles of HPC from different iPSC clones committing to CD8+ T cells or other cell lineages (monocytes/granulocytes, B lymphocytes/NK cells). Principal component analyses demonstrated a high similarity and low variability of transcription profiles within the replicates of HPC committed to the same cell lineage. In addition, distinct genome-wide shifts and differential gene expression profiles were detected in HPC committed to each specific cell differentiation pathway. Specifically, the HPC commit to CD8+ T cells utilized a diverse repertoire of modulators promoting development of T cell maturation, specific immune response regulation, memory T cells, cytotoxicity and interferon induction, which were significantly higher than shown in HPC that differentiate to other cell lineages. In parallel, specific repression genes were identified in the HPC commit to CD8+ T cells, which develop TGF-β receptor, rearrangement of Ig heavy chain genes and inhibitory receptors. The T cells differentiated were mainly CD45RO+ memory CTL and fully rejuvenated without immune checkpoints expression and regulatory T cells and with high anti-MM activities. Conclusions: These findings identify genetic and epigenetic mechanisms and regulatory elements, which play key roles during lineage specific commitment of HPC developed in iPSC into CD8+ CTL and help to further design a next generation of regenerative medicine that provide the appropriate signals for T cell lineage commitment from progenitor cells.
43
Bae, Jooeun, Shuichi Kitayama, Zach Herbert, Laurence Daheron, Nikhil C. Munshi, Shin Kaneko, Jerome Ritz, and Kenneth Carl Anderson. "Development of B-cell maturation antigen (BCMA)-specific CD8+ cytotoxic T lymphocytes using induced pluripotent stem cell technology for multiple myeloma." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 2542. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2542.
Full textAbstract:
2542 Background: A strategy for reversal of T cell exhaustion is reprograming of antigen-specific CTL to early lineage memory T cells with selective anti-tumor activities. To accomplish this goal, we epigenetically reprogrammed BCMA-specific CD8+ CTL to a pluripotent state through key defined transcription factors, established “induced Pluripotent Stem Cells (iPSC)” exhibiting transcriptional and epigenetic features, re-differentiated them back into antigen-specific CTL and evaluated their properties and functional activities against multiple myeloma (MM). Methods: Functionally activeIFN-g producing HLA-A2 heteroclitic BCMA72-80 (YLMFLLRKI)-specific CD8+ CTL were applied for iPSC via transduction of four reprogramming factors (OCT3/4, SOX2, KLF4, c-MYC). Upon characterization of the BCMA-specific iPSC with high pluripotency potential, embryoid body was formed from the iPSC and further polarized into mesoderm layer development as evidenced by upregulation of transcriptional regulators (ABCA4, BMP10, CDH5, FOXF1, HAND1, PLVAP, SNAI2, TBX3). Next, BCMA-specific embryoid body-derived hematopoietic progenitor cells (HPC; CD34+ CD43+/CD14- CD235a-) were sorted and induced to undergo T cell differentiation in the presence of Fc-DLL4 signaling and rectonectin. Results: Our RNAseq analyses demonstrated unique transcriptional profiles of HPC from different iPSC clones committing to CD8+ T cells or other cell lineages (monocytes/granulocytes, B lymphocytes/NK cells). Principal component analyses demonstrated a high similarity and low variability of transcription profiles within the replicates of HPC committed to the same cell lineage. In addition, distinct genome-wide shifts and differential gene expression profiles were detected in HPC committed to each specific cell differentiation pathway. Specifically, the HPC commit to CD8+ T cells utilized a diverse repertoire of modulators promoting development of T cell maturation, specific immune response regulation, memory T cells, cytotoxicity and interferon induction, which were significantly higher than shown in HPC that differentiate to other cell lineages. In parallel, specific repression genes were identified in the HPC commit to CD8+ T cells, which develop TGF-β receptor, rearrangement of Ig heavy chain genes and inhibitory receptors. The T cells differentiated were mainly CD45RO+ memory CTL and fully rejuvenated without immune checkpoints expression and regulatory T cells and with high anti-MM activities. Conclusions: These findings identify genetic and epigenetic mechanisms and regulatory elements, which play key roles during lineage specific commitment of HPC developed in iPSC into CD8+ CTL and help to further design a next generation of regenerative medicine that provide the appropriate signals for T cell lineage commitment from progenitor cells.
44
Alimova, Irina, Etienne Danis, Marla Weetall, Angela M. Pierce, Dong Wang, Natalie Serkova, Ilango Balakrishnan, et al. "ATRT-06. SMARCB1 LOSS DRIVEN NON-CANONICAL PRC1 ACTIVITY REGULATES DIFFERENTIATION IN ATYPICAL TERATOID RHABDOID TUMORS (ATRT)." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii276—iii277. http://dx.doi.org/10.1093/neuonc/noaa222.006.
Full textAbstract:
Abstract Loss of SMARCB1 is the hallmark genetic event that characterizes ATRT. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. To identify co-operating epigenetic factors, we performed an unbiased shRNA screen targeting 408 epigenetic/chromatin molecules in patient-derived ATRT cell lines and identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as essential for ATRT cell viability. Genetic and Chemical inhibition of BMI1 inhibited clonogenic potential and induced apoptosis in vitro. In vivo PTC 596 significantly decreased growth of intracranial orthotopic ATRT tumors as evaluated by T2 MRI imaging and significantly prolonged survival compared to control animals. Using RNA-seq and ChIP-Seq our studies show that BMI1 co-operates with SMARCB1 loss to suppress transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. We then used a doxycycline-inducible SMARCB1 expression system and performed Immunoprecipitation for BMI1, followed by and mass spectrometry analysis. In SMARCB1 deficient cells BMI1 forms a partial PRC1 complex devoid of DNA binding components. Re-expression of SMARCB1 activates two PRC1 chromatin localizing components CBX4 and CBX8. CBX4 is implicated DNA damage response, tumor angiogenesis and self-renewal. CBX8 activates lineage-specific genes during differentiation of ESC. Our data suggest that SMARCB1 deletion results in reprograming of BMI1 chromatin occupancy away from lineage specification by altering the components of the PRC1 complex. These studies identify the mechanistic basis of BMI1 co-operation with SMARCB1 loss in ATRT and establish BMI1 inhibition as a novel therapeutic approach in ATRT.
45
Tibana, Ramires, Octávio Franco, Rinaldo Pereira, James Navalta, and Jonato Prestes. "Exercise as an Effective Transgenerational Strategy to Overcome Metabolic Syndrome in the Future Generation: Are We There?" Experimental and Clinical Endocrinology & Diabetes 125, no. 06 (May 11, 2017): 347–52. http://dx.doi.org/10.1055/s-0042-120538.
Full textAbstract:
AbstractMetabolic syndrome (MetS) consist in a combination of cardiovascular risk factors including elevated blood pressure, dyslipidemia, insulin resistance, hyperglycemia and abdominal obesity. Exercise performed before, during and after pregnancy can exert positive effects to counteract MetS risk factors. Here this review aims to analyze the effects of exercise performed before (fathers and mothers) and after periconception (mothers) by using experimental models and its effects on MetS risk factors in offspring. All selected studies investigated the effects of aerobic exercise before, during and after periconception on MetS risk factors in offspring, while no studies utilizing resistance exercise were found. Exercise performed before, and after periconception exerted preventive effects in the offspring, with regards to MetS risk factors. However, more studies focusing on the dose-response of exercise before, and after periconception may reveal interesting results on MetS risk factor in offspring. Thus, the prevention from chronic degenerative diseases can be improved by mother exercise and might be associated with epigenetic mechanisms, such as DNA methylation, hPTMs (histone post translational modifications), non-coding RNAs (ex: MicroRNAs) which results phenotypic modifications by individual genome reprograming. Otherwise, results from paternal exercise are inconclusive at this time.
46
Masuda, Muneyuki, Hirofumi Omori, Kuniaki Sato, Josef Penninger, and Silvio Gutkind. "Abstract PO-063: Environment-induced YAP1 transcriptional reprogramming drives head and neck cancer." Clinical Cancer Research 29, no. 18_Supplement (September 15, 2023): PO—063—PO—063. http://dx.doi.org/10.1158/1557-3265.aacrahns23-po-063.
Full textAbstract:
Abstract Background: The biology of head and neck cancer (HNC) has been explained by the field carcinogenesis theory in which accumulated abnormalities (mainly gene mutations) caused by environmental stresses promote carcinogenesis. However, as clearly demonstrated by recent studies (Yokoyama et.al, Nature 2019; Hedberg et.al, JCI 2016), the genetic landscape of HNC (i.e., the loss-of-function mutations in tumor suppressor genes) fails to account for the onset and metastatic ability of HNC. In addition to being mutagen, environmental stresses induce oncogenic transcriptional programs (e.g., tissue regeneration). In this context, we have advanced our study based on a perspective that HNC is a symbiotic evolving system, highly dependent on transcriptional reprograming. Recently we succeeded to develop an ultra-rapid mouse carcinogenesis model (4W) induced by a transcriptional coactivator YAP1 (Omori et al, Sci Adv 2020) and are conducting integrative epigenetic analyses to elucidate how YAP1-induced transcriptional reprogramming drives HNC. Material and methods: Mouse tumors and a cell line and human HNC cell lines and tissue samples were subject to WES, WGBS, RNA-seq, Chip-seq (H3K27ac, YAP1, H3K9me2/3), and IHC. Results: YAP1-induced mouse tumors and cell lines demonstrated that YAP1 epigenetically causes carcinogenesis without affecting genome-wide chromatin confirmation, but inducing hypomethylation on the super enhancers (SE) of genes related to tissue regeneration (i.e., recapitulation of wounds that don’t heal condition). Poor prognosis was associated with YAP1-induced carcinogenesis gene module in the TCGA data (p = 0.00033) and with the level of YAP1nuclear protein in the 119 HNC samples (p = 0.0116). RNA-seq and Chip-seq with HNC cell lines showed that YAP1 is essential for the assembly of SE and that YAP1-related SE module including IL6 was associated with unfavorable survival in the TCGA data (p = 0.031). The existence of IL6-YAP1 feed-forward loop was confirmed in vitro assays. EEM and motif assays revealed that YAP1, collaborating with PITX2 transcriptional factor (TF), regulates TGF-beta-induced EMT and CAF, suggesting the involvement of YAP1 and PITX2 in the partial-EMT process, which was reported to play an important role in the nodal metastases of HNC (Puram et.al, Cell 2017). In the TCGA data, YAP1 target module demonstrated a significant correlation with p-EMT score or TGF-beta induced LRRC15 expressing CAF module. In the invasion front, YAP1 positive cancer cells co-existed with LRRC15 positive CAF. In vitro assays and Chip-seq on human HNC samples support the significance of collaboration of YAP1 and PITX2 in SE for nodal metastases. Co-expression of YAP1 plus PITX2 or BRD4 further worsened the prognosis than the individual factor alone. Conclusions: Collectively, our data indicate that YAP1-induced transcriptional reprograming, triggered and activated in the HNC specific tumor microenvironment, may function as a potent engine and thereby drive symbiotic evolution of HNC. Citation Format: Muneyuki Masuda, Hirofumi Omori, Kuniaki Sato, Josef Penninger, Silvio Gutkind. Environment-induced YAP1 transcriptional reprogramming drives head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-063.
47
Pereira, Marcelo de Souza Fernandes, Yasemin Sezgin, Aarohi Thakkar, and Dean Anthony Lee. "Tgfβ-Imprinting Decrease CD38 Expression and Lead to Metabolic Reprogramming on Primary NK Cell." Blood 136, Supplement 1 (November 5, 2020): 4. http://dx.doi.org/10.1182/blood-2020-143085.
Full textAbstract:
Transforming growth factor-β (TGF-β) plays an essential role in regulating immune responses through its immunossupressive effect on adaptive and innate immune cells. In addition, we and others have shown that alterations in cell-intrinsic metabolism profiles can significantly impact the function of immune cells. Previously, our group demonstrated that TGFβ-imprinting (TGFβi) decreases NK cell sensitivity to TGFβ through SMAD3 suppression and enhances a pro-inflammatory phenotype with hypersecretion of IFN-γ, TNF-α, and GM-CSF, which appeared to be mediated by an epigenetic mechanism. To evaluate this process, we conducted RNA-seq and ATAC-seq to evaluate the impact of chromosomal remodeling on gene expression. In addition to confirming low SMAD3 transcription, this data showed that TGFβi NK cells have decreased CD38 expression, which we confirmed at the protein level. Since CD38 is an ectoenzyme that regulates nicotinamide adenine dinucleotide (NAD+), a critical component of OXPHOS in both T and NK cells, we examined the effect of TGFβi on NK cell metabolism. TGFβi primary NK cells were generated from peripheral blood of healthy donors as previously described, and using a mitochondrial stress test assay, we observed higher oxygen consumption rates (OCR). However, in the glycolysis stress test assay we observed comparable extracellular acidification rates (ECAR) between Standard expanded and TGFbi NK cells, resulting in higher OCR/ECAR ratios in TGFbi NK cells. Since TGFβ has been shown to induce fragmented mitochondria, and inhibition of mitochondrial fragmentation improved mitochondrial metabolism, we evaluated subcellular structure of TGFβi NK cellsby transmission electron microscopy (TEM). We found no difference in mitochondrial fragmentation between STD and TGFβi NK cells. Together, these results show that TGFβi induces epigenetic reprograming of NK cells that results in increased OXPHOS through CD38 suppression. Moreover, the decreases CD38 expression in TGFβi NK cells could be a promising non-genetic alternative to generating CD38-negative NK cells to avoid fratricide in combination with DARA Figure Disclosures Lee: Kiadis Pharma Netherlands B.V: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
48
Chiang, Chi-Ling, Frank W. Frissora, Zhiliang Xie, Xiaomeng Huang, Rajeswaran Mani, Sivasubramanian Baskar, Christoph Rader, et al. "Immunoliposomal Delivery of Mir-29b By Targeting Tumor Antigen ROR1 Induces Epigenetic Reprograming in Human-ROR1-Expressed Mouse Model of Chronic Lymphocytic Leukemia." Blood 126, no. 23 (December 3, 2015): 1743. http://dx.doi.org/10.1182/blood.v126.23.1743.1743.
Full textAbstract:
Abstract Chronic lymphocytic leukemia (CLL), characterized by accumulation of CD5+CD19+sIgM+ B lymphocytes in peripheral blood and lymphoid organs, is classified into indolent and aggressive forms. Patients with indolent CLL generally survive 5 to 10 years and do not require treatment until severe symptoms, while those with aggressive CLL show resistant to standard treatment and survive less than 24 months. While emerging B cell antigen receptor directed therapies are promising, resistance to such therapies pose problems warranting novel therapeutic approaches. MicroRNA (miR) profiling revealed lower expression of miR-29b in aggressive CLL associated with survival, drug resistance and poor prognosis via its up-regulation of anti-apoptotic proteins myeloid leukemia cell differentiation protein 1 (Mcl1) and oncogenic T-cell leukemia 1 (Tcl1). Thus, specific overexpression of miR-29b in B-CLL cells could be a potential therapy for aggressive CLL patients. Despite the promise, short circulation half-life, limited cellular uptake and off-target effects on non-desirable tissues pose a challenge for miR-based therapies. To promote efficiency and specificity of miR-29b delivery, we developed neutral immunonanoparticles with selectivity to CLL via targeting tumor antigen ROR1, which is expressed in over 95% of CLL but not normal B cells. We optimized a novel 2A2-immunoliposome (2A2-ILP) recognizing surface ROR1 on primary CLL cell to promote internalization and miR-29b uptake (n=6, p=0.042*). About 20-fold increased uptake of miR-29b was achieved with 2A2-ILP-miR-29b formulation compared to control. Further ROR1 targeted delivery of miR29b resulted in significant downregulation of DNMT1 and DNMT3a mRNA and protein (n=3, DNMT1: p= 0.0115*; DNMT3a: p=0.0231*, SP1; p=0.0031**) in primary CLL cells and a human CLL cell line OSU-CLL. Consistent with the downregulation of DNMTs, decreased global DNA methylation was observed in OSU-CLL cell line one week post- treatment with 2A2-ILP-miR-29b (n=3, p=0.0003***). To further study the in vivo ROR1-targeting efficiency of 2A2-ILP-miR-29b, we used our recently described Eµ-hROR1x Tcl1 CLL mouse model that develops CLL like disease with human ROR1 antigen in leukemic CD19+CD5+ B cells. Using hROR1+CD19+CD5+ leukemic cell engraftment model, we showed significant in-vivo efficacy of ROR1-ILP-miR-29b formulation associated with a) decreased number of circulating leukemic B220+CD5+ cells b) reduced splenomegaly (p=0.0461*, 2A2-29b: n=9; PBS: n=8) c) with extended survival (p=0.0075**, 2A2-29b: n=9; IgG-29b: n=7; 2A2-SC: n=7; PBS: n=8). In summary, 2A2-ILP effectively delivered functional miR-29b, resulting in downregulation of DNMT1 and DNMT3a, reduction of hypermethylation and anti-leukemic activity. Ongoing studies are aimed at understanding miR-29b mediated in-vivo methylome reprograming using our novel hROR1xTcl1 transgenic mouse model and ROR1-targeted miR-29b delivery formulation. Figure 1. Figure 1. Disclosures Byrd: Acerta Pharma BV: Research Funding.
49
Baranovski, Boris M., Gabriella S. Freixo-Lima, Eli C. Lewis, and Peleg Rider. "T Helper Subsets, Peripheral Plasticity, and the Acute Phase Protein,α1-Antitrypsin." BioMed Research International 2015 (2015): 1–14. http://dx.doi.org/10.1155/2015/184574.
Full textAbstract:
The traditional model of T helper differentiation describes the naïve T cell as choosing one of several subsets upon stimulation and an added reciprocal inhibition aimed at maintaining the chosen subset. However, to date, evidence is mounting to support the presence of subset plasticity. This is, presumably, aimed at fine-tuning adaptive immune responses according to local signals. Reprograming of cell phenotype is made possible by changes in activation of master transcription factors, employing epigenetic modifications that preserve a flexible mode, permitting a shift between activation and silencing of genes. The acute phase response represents an example of peripheral changes that are critical in modulating T cell responses.α1-antitrypsin (AAT) belongs to the acute phase responses and has recently surfaced as a tolerogenic agent in the context of adaptive immune responses. Nonetheless, AAT does not inhibit T cell responses, nor does it shutdown inflammation per se; rather, it appears that AAT targets non-T cell immunocytes towards changing the cytokine environment of T cells, thus promoting a regulatory T cell profile. The present review focuses on this intriguing two-way communication between innate and adaptive entities, a crosstalk that holds important implications on potential therapies for a multitude of immune disorders.
50
Byrne, Kristen A., Julian M. Trachsel, Zahra F. Bond, Jamison R. Slate, Brian J. Kerr, Bradley L. Bearson, Shawn M. Bearson, and Crystal L. Loving. "Dietary β-glucan reduced Salmonella shedding, shifted intestinal microbiome, and altered intestinal integrity." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 92.15. http://dx.doi.org/10.4049/jimmunol.204.supp.92.15.
Full textAbstract:
Abstract β-glucan is a prebiotic dietary fiber with immune and microbiota modulating properties. Dietary β-glucan can shift intestinal microbial populations and concentrations of short chain fatty acids (notably, butyrate and propionate), which may alter local populations of regulatory T-cells. Additionally, epigenetic reprograming of monocytes by β-glucan impacts subsequent monocyte responses to heterologous agonists, a form of innate training. Here, β-glucan from Saccharomyces cerevisiae was evaluated as a non-antibiotic dietary additive to limit shedding of the foodborne pathogen, Salmonella enterica server Typhimurium, via changes to the intestinal microbiota, intestinal integrity, and/or the local and peripheral immune system in pigs. Overall Salmonella shedding and cecal mucosa burden was significantly reduced in pigs fed dietary β-glucan compared to Salmonella challenged pigs on control diet. Shifts in microbial communities were associated with reduced Salmonella burden, as pigs fed β-glucan exhibited enhanced cecal epithelial barrier function, altered fecal bacterial communities, and increased short chain fatty acid concentrations. However, no significant differences in regulatory T cell population nor ex vivo monocyte responses were found between groups. Collectively, the non-antibiotic dietary additive β-glucan altered microbial communities and host epithelial cell function in conjunction with reduced Salmonella shedding in pigs.