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Al-Janabi, Ismail. "Therapeutic Targeting of the Regulators of Cancer Epigenomes." Al-Rafidain Journal of Medical Sciences ( ISSN 2789-3219 ) 5 (July 1, 2023): 1–13. http://dx.doi.org/10.54133/ajms.v5i.128.
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Aim: To assess the value of targeting the various molecules that regulate the epigenome in the management of cancer. Method: Peer-reviewed articles were examined in PubMed, Google Scholar, and ResearchGate search tools using keywords given in the manuscript. Main points: Three major epigenomic modifications, namely DNA methylation, histone methylation, and histone acetylation, attracted the most research interest and led to a few globally approved drugs for the treatment of various malignancies. The DNA methylation profiles of cancer have been successfully employed in many aspects of the management of this disease. Conclusion: Epigenomic profiling of cancer specimens has already been successfully employed in the management of cancer in a handful of specialized clinics, and this application could be extended further following more in-depth investigations in this field.
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Paul, Aswathy Mary, Madhavan Radhakrishna Pillai, and Rakesh Kumar. "Prognostic Significance of Dysregulated Epigenomic and Chromatin Modifiers in Cervical Cancer." Cells 10, no. 10 (October 5, 2021): 2665. http://dx.doi.org/10.3390/cells10102665.
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To broaden the understanding of the epigenomic and chromatin regulation of cervical cancer, we examined the status and significance of a set of epigenomic and chromatin modifiers in cervical cancer using computational biology. We observed that 61 of 917 epigenomic and/or chromatin regulators are differentially upregulated in human cancer, including 25 upregulated in invasive squamous cell carcinomas and 29 in cervical intraepithelial neoplasia 3 (CIN3), of which 14 are upregulated in cervical intraepithelial neoplasia 2 (CIN2). Interestingly, 57 of such regulators are uniquely upregulated in cervical cancer, but not ovarian and endometrial cancers. The observed overexpression of 57 regulators was found to have a prognostic significance in cervical cancer. The collective overexpression of these regulators, as well as its subsets belonging to specific histone modifications and corresponding top ten positively co-overexpressed genes, correlated with reduced survival of patients with high expressions of the tested overexpressed regulators compared to cases with low expressions. Using cell-dependency datasets from human cervical cancer cells, we found that 20 out of 57 epigenomic and chromatin regulators studied here appeared to be essential genes, as the depletion of these genes was accompanied by the loss in cellular viability. In brief, the results presented here provide further insights into the role of epigenomic and chromatin regulators in the oncobiology of cervical cancer and broaden the list of new potential molecules of therapeutic importance.
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Schmitz, Ulf, Jaynish S. Shah, Bijay P. Dhungel, Geoffray Monteuuis, Phuc-Loi Luu, Veronika Petrova, Cynthia Metierre, et al. "Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients." Cancers 12, no. 12 (December 11, 2020): 3738. http://dx.doi.org/10.3390/cancers12123738.
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Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukaemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Using RNA sequencing and whole-genome bisulfite sequencing, we profiled samples from chronic-phase CML patients at diagnosis and remission and compared these to healthy donors. Remarkably, our analyses revealed that abnormal splicing distinguishes remission samples from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis samples. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease.
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Zhou, Huaijun. "97 Dissection of Evolution of Cis-Regulatory Elements and Its Application on Genetic Control of Complex Traits in Farm Animals." Journal of Animal Science 101, Supplement_3 (November 6, 2023): 51–52. http://dx.doi.org/10.1093/jas/skad281.063.
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Abstract Functional Annotation of Animal Genomes (FAANG) has made significant progress on the improvement of the annotation of the functional elements, particularly non-coding regions in farm animal genomes. Different epigenomes including ChIP-seq for 4 histone marks, ATAC-seq, CTCF-seq, RNA-seq, and Hi-C across different tissues in different animal species were generated. Thousands of cis-regulatory elements including promoters and enhancers across different tissues in different species were identified and annotated. A comprehensive characterization and comparison of cis-regulatory elements across tissues and species can help us understand the genetic and evolutionary basis of complex phenotypes. Yet, attempts to dissect the evolution of regulatory elements have generally been small, both regarding the number of tissues and species compared. We demonstrate that genomic variants associated with complex traits and adaptive evolution in farm animals are significantly enriched in active promoters and enhancers. Further analysis suggests that the regulators were significantly enriched in evolutionary breakpoint regions (EBRs) in a tissue-specific and regulator-specific manner. Furthermore, we reveal distinct tissue-specific regulatory elements play important roles in domestication processes. Finally, we provide biological insights on tissue-specific regulatory conservation, and by integrating genome-wide association studies on complex traits, we demonstrate that comparative epigenomic analysis enhances our interpretations of complex traits variations in farm animals and provides novel insights on the role of regulatory elements on the functional conservation across species.
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Tseng, Yen-Tzu, Hung-Fu Liao, Chih-Yun Yu, Chu-Fan Mo, and Shau-Ping Lin. "Epigenetic factors in the regulation of prospermatogonia and spermatogonial stem cells." REPRODUCTION 150, no. 3 (September 2015): R77—R91. http://dx.doi.org/10.1530/rep-14-0679.
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Appropriate regulation of epigenome within cells is crucial for the determination of cell fate and contributes to the lifelong maintenance of tissue homeostasis. Epigenomic re-establishment during embryonic prospermatogonia development and fine-tune of the epigenetic landscape in postnatal spermatogonial stem cells (SSCs) are two key processes required for functional male germ cell formation. Repression of re-activated transposons and male germline-specific epigenome establishment occur in prospermatogonia, whereas modulations of the epigenetic landscape is important for SSC self-renewal and differentiation to maintain the stem cell pool and support long-term sperm production. Here, we describe the impact of epigenome-related regulators and small non-coding RNAs as well as the influence of epigenome modifications that result from extrinsic signaling for controlling the decision between self-renewal, differentiation and survival in mouse prospermatogonia and SSCs. This article provides a review of epigenome-related molecules involved in cell fate determination in male germ cells and discusses the intriguing questions that arise from these studies.
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Deng, Xian, Xianwei Song, Liya Wei, Chunyan Liu, and Xiaofeng Cao. "Epigenetic regulation and epigenomic landscape in rice." National Science Review 3, no. 3 (September 1, 2016): 309–27. http://dx.doi.org/10.1093/nsr/nww042.
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Abstract Epigenetic regulation has been implicated in the control of complex agronomic traits in rice (Oryza sativa), a staple food crop and model monocot plant. Recent advances in high-throughput sequencing and the moderately complex genome of rice have made it possible to study epigenetic regulation in rice on a genome-wide scale. This review discusses recent advances in our understanding of epigenetic regulation in rice, with an emphasis on the roles of key epigenetic regulators, the epigenomic landscape, epigenetic variation, transposon repression, and plant development.
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Rada-Iglesias, Alvaro, Ruchi Bajpai, Sara Prescott, Samantha A. Brugmann, Tomek Swigut, and Joanna Wysocka. "Epigenomic Annotation of Enhancers Predicts Transcriptional Regulators of Human Neural Crest." Cell Stem Cell 11, no. 5 (November 2012): 633–48. http://dx.doi.org/10.1016/j.stem.2012.07.006.
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Smetanina, Mariya A., Valeria A. Korolenya, Alexander E. Kel, Ksenia S. Sevostyanova, Konstantin A. Gavrilov, Andrey I. Shevela, and Maxim L. Filipenko. "Epigenome-Wide Changes in the Cell Layers of the Vein Wall When Exposing the Venous Endothelium to Oscillatory Shear Stress." Epigenomes 7, no. 1 (March 20, 2023): 8. http://dx.doi.org/10.3390/epigenomes7010008.
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Epigenomic changes in the venous cells exerted by oscillatory shear stress towards the endothelium may result in consolidation of gene expression alterations upon vein wall remodeling during varicose transformation. We aimed to reveal such epigenome-wide methylation changes. Primary culture cells were obtained from non-varicose vein segments left after surgery of 3 patients by growing the cells in selective media after magnetic immunosorting. Endothelial cells were either exposed to oscillatory shear stress or left at the static condition. Then, other cell types were treated with preconditioned media from the adjacent layer’s cells. DNA isolated from the harvested cells was subjected to epigenome-wide study using Illumina microarrays followed by data analysis with GenomeStudio (Illumina), Excel (Microsoft), and Genome Enhancer (geneXplain) software packages. Differential (hypo-/hyper-) methylation was revealed for each cell layer’s DNA. The most targetable master regulators controlling the activity of certain transcription factors regulating the genes near the differentially methylated sites appeared to be the following: (1) HGS, PDGFB, and AR for endothelial cells; (2) HGS, CDH2, SPRY2, SMAD2, ZFYVE9, and P2RY1 for smooth muscle cells; and (3) WWOX, F8, IGF2R, NFKB1, RELA, SOCS1, and FXN for fibroblasts. Some of the identified master regulators may serve as promising druggable targets for treating varicose veins in the future.
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Boix, Carles A., Benjamin T. James, Yongjin P. Park, Wouter Meuleman, and Manolis Kellis. "Regulatory genomic circuitry of human disease loci by integrative epigenomics." Nature 590, no. 7845 (February 3, 2021): 300–307. http://dx.doi.org/10.1038/s41586-020-03145-z.
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AbstractAnnotating the molecular basis of human disease remains an unsolved challenge, as 93% of disease loci are non-coding and gene-regulatory annotations are highly incomplete1–3. Here we present EpiMap, a compendium comprising 10,000 epigenomic maps across 800 samples, which we used to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators and downstream target genes. We used this resource to annotate 30,000 genetic loci that were associated with 540 traits4, predicting trait-relevant tissues, putative causal nucleotide variants in enriched tissue enhancers and candidate tissue-specific target genes for each. We partitioned multifactorial traits into tissue-specific contributing factors with distinct functional enrichments and disease comorbidity patterns, and revealed both single-factor monotropic and multifactor pleiotropic loci. Top-scoring loci frequently had multiple predicted driver variants, converging through multiple enhancers with a common target gene, multiple genes in common tissues, or multiple genes and multiple tissues, indicating extensive pleiotropy. Our results demonstrate the importance of dense, rich, high-resolution epigenomic annotations for the investigation of complex traits.
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kong, ranran, Ayushi S. Patel, Takashi Sato, Seungyeul Yoo, Abhilasha Sinha, Yang Tian, Feng Jiang, et al. "Abstract 5709: Transcriptional circuitry of NKX2-1 and SOX1 defines a previously unrecognized lineage subtype of small cell lung cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5709. http://dx.doi.org/10.1158/1538-7445.am2022-5709.
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Abstract Introduction: The current molecular classification of small cell lung cancer (SCLC) based on expression of four lineage transcription factors, SCLC-A (ASCL1), SCLC-N (NEUROD1), SCLC-P (POU2F3), and SCLC-Y (YAP1) still leaves its major subtype SCLC-A as a large heterogeneous group, necessitating more precise characterization of lineage subclasses. Experimental procedure: To refine the current SCLC classification and to identify specific lineage features of the SCLC subtypes, we performed unsupervised hierarchical clustering of H3K27ac profiles on transcriptional regulators from 25 SCLC cell lines and determined the epigenomic features for each cluster. Functional significance of the transcriptional lineage regulators for the identified cluster was evaluated by cell growth, apoptosis and xenograft using CRISPR-Cas9-mediated deletion. The specific cistromic profiles by ChIP-seq and its functional transcriptional partners using co-immunoprecipitation followed by mass spectrometry were determined to reveal their functional output in the identified subtype. Rb1fl/flTrp53fl/fl and Rb1fl/flTrp53fl/flNkx2-1fl/fl genetic engineered mouse model were generated to explore the function of Nkx2-1 in tumor initiation and differentiation. H3K27ac profiles were further analyzed to reveal 6 human SCLC specimen and 20 mice tumors epigenomic landscapes. Summary: We identified previously uncharacterized epigenomic sub-clusters of the major SCLC-A subtype, named SCLC-A1 and SCLC-A2. SCLC-A1 was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-A1, where it maintains neural lineage rather than pulmonary epithelial identity. We further found maintenance of this neural identity in SCLC-A1 is mediated by collaborative transcriptional activity with another neuronal transcriptional factor SOX1. ? Conclusions: We comprehensively describe an additional epigenomic heterogeneity of the major SCLC-A subtype, and define SCLC-A1 subtype by the core regulatory circuitry representing NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain a neuronal linage state. Citation Format: ranran kong, Ayushi S. Patel, Takashi Sato, Seungyeul Yoo, Abhilasha Sinha, Yang Tian, Feng Jiang, Charles A. Powell, Eric Snyder, Jiantao Jiang, Shaomin Li, Hideo Watanabe. Transcriptional circuitry of NKX2-1 and SOX1 defines a previously unrecognized lineage subtype of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5709.
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Brunmeir, Reinhard, Jingyi Wu, Xu Peng, Sun-Yee Kim, Sofi G. Julien, Qiongyi Zhang, Wei Xie, and Feng Xu. "Comparative Transcriptomic and Epigenomic Analyses Reveal New Regulators of Murine Brown Adipogenesis." PLOS Genetics 12, no. 12 (December 6, 2016): e1006474. http://dx.doi.org/10.1371/journal.pgen.1006474.
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Golimbet, V. E., A. K. Golov, and N. V. Kondratyev. "Post-GWAS era in genetics of schizophrenia." V.M. BEKHTEREV REVIEW OF PSYCHIATRY AND MEDICAL PSYCHOLOGY, no. 4-1 (December 9, 2019): 6–7. http://dx.doi.org/10.31363/2313-7053-2019-4-1-6-7.
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Genome-wide association studies (GWASs) discovered multiple genetic variants associated with schizophrenia. Te next step (post-GWAS analysis) is aimed at identifying the causal genetic variants and biological mechanisms underlying the associations with disease risk. Te following strategies are considered: the study of transcriptional regulation in neuronal human cells and the use of epigenomic information for searching for regulatory elements involved in the pathogenesis of schizophrenia. Te frst strategy includes identifcation of neuronal enhancers, mapping of potential target genes and functional confrmation of enhancer-promoter interactions. Te second approach is focused on the identifcation of transcriptional factors, which appear to be master regulators of expression.
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Lu, Jia, Xiaoyi Cao, and Sheng Zhong. "EpiAlignment: alignment with both DNA sequence and epigenomic data." Nucleic Acids Research 47, W1 (May 22, 2019): W11—W19. http://dx.doi.org/10.1093/nar/gkz426.
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Abstract Comparative epigenomics, which subjects both epigenome and genome to interspecies comparison, has become a powerful approach to reveal regulatory features of the genome. Thus elucidated regulatory features surpass the information derived from comparison of genomic sequences alone. Here, we present EpiAlignment, a web-based tool to align genomic regions with both DNA sequence and epigenomic data. EpiAlignment takes DNA sequence and epigenomic profiles derived by ChIP-seq from two species as input data, and outputs the best semi-global alignments. These alignments are based on EpiAlignment scores, computed by a dynamic programming algorithm that accounts for both sequence alignment and epigenome similarity. For timely response, the EpiAlignment web server automatically initiates up to 140 computing threads depending on the size of user input data. For users’ convenience, we have pre-compiled the comparable human and mouse epigenome datasets in matched cell types and tissues from the Roadmap Epigenomics and ENCODE consortia. Users can either upload their own data or select pre-compiled datasets as inputs for EpiAlignment analyses. Results are presented in graphical and tabular formats where the entries can be interactively expanded to visualize additional features of these aligned regions. EpiAlignment is available at https://epialign.ucsd.edu/.
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Bond, Danielle R., Kumar Uddipto, Anoop K. Enjeti, and Heather J. Lee. "Single-cell epigenomics in cancer: charting a course to clinical impact." Epigenomics 12, no. 13 (July 2020): 1139–51. http://dx.doi.org/10.2217/epi-2020-0046.
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Cancer is a disease of global epigenetic dysregulation. Mutations in epigenetic regulators are common events in multiple cancer types and epigenetic therapies are emerging as a treatment option in several malignancies. A major challenge for the clinical management of cancer is the heterogeneous nature of this disease. Cancers are composed of numerous cell types and evolve over time. This heterogeneity confounds decisions regarding treatment and promotes disease relapse. The emergence of single-cell epigenomic technologies has introduced the exciting possibility of linking genetic and transcriptional heterogeneity in the context of cancer biology. The next challenge is to leverage these tools for improved patient outcomes. Here we consider how single-cell epigenomic technologies may address the current challenges faced by cancer clinicians.
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Binder, Moritz, Alexandre Gaspar Maia, Ryan M. Carr, Christopher Pin, Kurt Berger, Bonnie Alver, Keith Robertson, David Marks, Martin Fernandez-Zapico, and Mrinal M. Patnaik. "Epigenomic Determinants of Transcriptional Activity in ASXL1-Mutant Chronic Myelomonocytic Leukemia." Blood 134, Supplement_1 (November 13, 2019): 2987. http://dx.doi.org/10.1182/blood-2019-123191.
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Introduction: Truncating mutations in the Additional Sex Combs-Like 1 (ASXL1) gene are associated with a proliferative disease phenotype and poor survival outcomes across the spectrum of myeloid malignancies including chronic myelomonocytic leukemia (CMML). ASXL1 is thought to act as a chromatin modifier regulating transcriptional activity, however the exact mechanisms and resulting chromatin states remain controversial. We interrogated the epigenome of 16 patients with ASXL1-mutant and -wildtype CMML using a multiomics approach. Methods: Bone marrow mononuclear cells from patients with CMML (8 ASXL1-mutant, 8 -wildtype) were subjected to targeted NGS of DNA, whole transcriptome shotgun sequencing (RNA-seq), immunoprecipitation (IP) of DNA (hydroxy-)methyl residues (DIP-seq), IP of the histone modifications H3K4me1, H3K4me3, and H3K27me3 (ChIP-seq), and DNA transposase accessibility studies (ATAC-seq). After quality control all samples were sequenced on an Illumina HiSeq 4000 before further processing and data analysis. Global assessments of DNA (hydroxy-)methylation, DNA accessibility, and histone modifications between ASXL1-mutant and -wildtype CMML were performed. Differential gene expression was performed to define the up-regulated genes in ASXL1-mutant disease. The promoter regions of these up-regulated genes (defined as transcription start site ±3kb) were compared using the aforementioned multiomics approach. Epigenomic modification of the promoter region facilitating up-regulation of transcription was defined as the presence of a signal peak in ASXL1-mutant disease (in the absence of a signal peak in -wildtype disease) or 25% increase in a common signal peak (H3K4me1/3, 5hmC), the presence of a unique signal peak in ASXL1-mutant disease (ATAC), or the absence of a signal peak in ASXL1-mutant disease (in the presence of a signal peak in -wildtype disease), or 25% decrease in a common signal peak (H3K27me3, 5mC). Results: Sixteen patients with CMML, median age 69 years (48 - 77), 63% male, were included. Half of the patients had proliferative disease (pCMML) and half of them had truncating frameshift mutations in ASXL1 (heatmap). All ASXL1 variant allele frequencies were compatible with heterozygosity (31 - 48%). The burden of co-mutations was similar between ASXL1-wildtype and ASXL1-mutant disease (21 versus 23 per group; no difference in the median number of co-mutations, p = 0.684). The spectrum of co-mutations was typical for CMML, involving spliceosome components, epigenetic regulators, chromatin regulators, and cell signaling molecules (heatmap). There was a predominant up-regulation of gene expression in ASXL1-mutant patients: 707 genes up- and 124 down-regulated (volcano plot, FDR < 0.05 for all genes). Functional annotation of the up-regulated genes showed cell division, mitotic nuclear division, sister chromatid cohesion, DNA replication, and G1/S transition to be the 5 most enriched processes (accounting for 29% of all up-regulated genes, FDR < 1x10-10 for all terms). The up-regulated genes included several potential therapeutic targets and HOXA family members (including HOXA9). There were global increases in H3K4me1/3, 5mC, and 5hmC, decreases in H3K27me3, as well as a more relaxed chromatin conformation (bar graphs). Many of these epigenomic changes affected non-coding regions. When focusing on the promoter regions of the 707 up-regulated genes there was evidence of one or more of the interrogated epigenomic mechanisms facilitating transcription for 519 of the genes (73%). The most abundant mechanism was histone modification, followed by changes in DNA (hydroxy-)methylation, and increased chromatin accessibility, with considerable overlap (Venn diagram). For HOXA9, a known driver of leukemogenesis, the data supported a loss of H3K27me3 as the most prominent among the interrogated epigenomic regulatory mechanisms (average signal tracks). Conclusions: The transcriptome and chromatin conformation of ASXL1-mutant CMML are skewed towards proliferation and mirror the aggressive disease phenotype observed in practice. There is evidence of histone modification as well as changes in DNA methylation, and chromatin conformation facilitating transcriptional activity including known leukemogenic drivers. Additional regulatory mechanisms such as gene body methylation and enhancer elements require further exploration. Figure Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.
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Cescon, DW. "Abstract ES13-3: Novel epigenomic targets in TNBC." Cancer Research 82, no. 4_Supplement (February 15, 2022): ES13–3—ES13–3. http://dx.doi.org/10.1158/1538-7445.sabcs21-es13-3.
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Abstract Triple negative breast cancer is a heterogenous disease, characterized by a dearth of recurrent actionable genetic alterations. Epigenetic alterations have been implicated in the pathogenesis of triple negative breast cancer, as well as in the acquisition of drug resistance, which is a commonly observed phenomenon and persisting clinical challenge. An expanding array of tools for epigenomic characterization, together with novel selective inhibitors of epigenetic regulators are enabling new opportunities to identify and target these processes in triple negative breast cancer. Examples of recent and emerging therapeutic strategies using conventional therapies and epigenetic-targeted agents to exploit these vulnerabilities in triple negative breast cancer will be discussed. Citation Format: DW Cescon. Novel epigenomic targets in TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES13-3.
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Blank-Giwojna, Alena, Anna Postepska-Igielska, and Ingrid Grummt. "lncRNA KHPS1 Activates a Poised Enhancer by Triplex-Dependent Recruitment of Epigenomic Regulators." Cell Reports 26, no. 11 (March 2019): 2904–15. http://dx.doi.org/10.1016/j.celrep.2019.02.059.
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Yildirim, Ferah, Christopher W. Ng, Vincent Kappes, Tobias Ehrenberger, Siobhan K. Rigby, Victoria Stivanello, Theresa A. Gipson, et al. "Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington’s disease." Proceedings of the National Academy of Sciences 116, no. 49 (November 19, 2019): 24840–51. http://dx.doi.org/10.1073/pnas.1908113116.
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Huntington’s disease (HD) is a chronic neurodegenerative disorder characterized by a late clinical onset despite ubiquitous expression of the mutant Huntingtin gene (HTT) from birth. Transcriptional dysregulation is a pivotal feature of HD. Yet, the genes that are altered in the prodromal period and their regulators, which present opportunities for therapeutic intervention, remain to be elucidated. Using transcriptional and chromatin profiling, we found aberrant transcription and changes in histone H3K27acetylation in the striatum of R6/1 mice during the presymptomatic disease stages. Integrating these data, we identified the Elk-1 transcription factor as a candidate regulator of prodromal changes in HD. Exogenous expression of Elk-1 exerted beneficial effects in a primary striatal cell culture model of HD, and adeno-associated virus-mediated Elk-1 overexpression alleviated transcriptional dysregulation in R6/1 mice. Collectively, our work demonstrates that aberrant gene expression precedes overt disease onset in HD, identifies the Elk-1 transcription factor as a key regulator linked to early epigenetic and transcriptional changes in HD, and presents evidence for Elk-1 as a target for alleviating molecular pathology in HD.
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Wattacheril, Julia J., Srilakshmi Raj, David A. Knowles, and John M. Greally. "Using epigenomics to understand cellular responses to environmental influences in diseases." PLOS Genetics 19, no. 1 (January 19, 2023): e1010567. http://dx.doi.org/10.1371/journal.pgen.1010567.
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It is a generally accepted model that environmental influences can exert their effects, at least in part, by changing the molecular regulators of transcription that are described as epigenetic. As there is biochemical evidence that some epigenetic regulators of transcription can maintain their states long term and through cell division, an epigenetic model encompasses the idea of maintenance of the effect of an exposure long after it is no longer present. The evidence supporting this model is mostly from the observation of alterations of molecular regulators of transcription following exposures. With the understanding that the interpretation of these associations is more complex than originally recognised, this model may be oversimplistic; therefore, adopting novel perspectives and experimental approaches when examining how environmental exposures are linked to phenotypes may prove worthwhile. In this review, we have chosen to use the example of nonalcoholic fatty liver disease (NAFLD), a common, complex human disease with strong environmental and genetic influences. We describe how epigenomic approaches combined with emerging functional genetic and single-cell genomic techniques are poised to generate new insights into the pathogenesis of environmentally influenced human disease phenotypes exemplified by NAFLD.
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Rovira, Meritxell, Goutham Atla, Miguel Angel Maestro, Vane Grau, Javier García-Hurtado, Maria Maqueda, Jose Luis Mosquera, et al. "REST is a major negative regulator of endocrine differentiation during pancreas organogenesis." Genes & Development 35, no. 17-18 (August 12, 2021): 1229–42. http://dx.doi.org/10.1101/gad.348501.121.
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Multiple transcription factors have been shown to promote pancreatic β-cell differentiation, yet much less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic Rest knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts and induced β-cell-specific genes in human adult duct-derived organoids. We also defined genomic sites that are bound and repressed by REST in the embryonic pancreas. Our findings show that REST-dependent inhibition ensures a balanced production of endocrine cells from embryonic pancreatic progenitors.
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Torres-Campana, Daniela, Béatrice Horard, Sandrine Denaud, Gérard Benoit, Benjamin Loppin, and Guillermo A. Orsi. "Three classes of epigenomic regulators converge to hyperactivate the essential maternal gene deadhead within a heterochromatin mini-domain." PLOS Genetics 18, no. 1 (January 4, 2022): e1009615. http://dx.doi.org/10.1371/journal.pgen.1009615.
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The formation of a diploid zygote is a highly complex cellular process that is entirely controlled by maternal gene products stored in the egg cytoplasm. This highly specialized transcriptional program is tightly controlled at the chromatin level in the female germline. As an extreme case in point, the massive and specific ovarian expression of the essential thioredoxin Deadhead (DHD) is critically regulated in Drosophila by the histone demethylase Lid and its partner, the histone deacetylase complex Sin3A/Rpd3, via yet unknown mechanisms. Here, we identified Snr1 and Mod(mdg4) as essential for dhd expression and investigated how these epigenomic effectors act with Lid and Sin3A to hyperactivate dhd. Using Cut&Run chromatin profiling with a dedicated data analysis procedure, we found that dhd is intriguingly embedded in an H3K27me3/H3K9me3-enriched mini-domain flanked by DNA regulatory elements, including a dhd promoter-proximal element essential for its expression. Surprisingly, Lid, Sin3a, Snr1 and Mod(mdg4) impact H3K27me3 and this regulatory element in distinct manners. However, we show that these effectors activate dhd independently of H3K27me3/H3K9me3, and that dhd remains silent in the absence of these marks. Together, our study demonstrates an atypical and critical role for chromatin regulators Lid, Sin3A, Snr1 and Mod(mdg4) to trigger tissue-specific hyperactivation within a unique heterochromatin mini-domain.
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Zibetti, Cristina. "Deciphering the Retinal Epigenome during Development, Disease and Reprogramming: Advancements, Challenges and Perspectives." Cells 11, no. 5 (February 25, 2022): 806. http://dx.doi.org/10.3390/cells11050806.
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Retinal neurogenesis is driven by concerted actions of transcription factors, some of which are expressed in a continuum and across several cell subtypes throughout development. While seemingly redundant, many factors diversify their regulatory outcome on gene expression, by coordinating variations in chromatin landscapes to drive divergent retinal specification programs. Recent studies have furthered the understanding of the epigenetic contribution to the progression of age-related macular degeneration, a leading cause of blindness in the elderly. The knowledge of the epigenomic mechanisms that control the acquisition and stabilization of retinal cell fates and are evoked upon damage, holds the potential for the treatment of retinal degeneration. Herein, this review presents the state-of-the-art approaches to investigate the retinal epigenome during development, disease, and reprogramming. A pipeline is then reviewed to functionally interrogate the epigenetic and transcriptional networks underlying cell fate specification, relying on a truly unbiased screening of open chromatin states. The related work proposes an inferential model to identify gene regulatory networks, features the first footprinting analysis and the first tentative, systematic query of candidate pioneer factors in the retina ever conducted in any model organism, leading to the identification of previously uncharacterized master regulators of retinal cell identity, such as the nuclear factor I, NFI. This pipeline is virtually applicable to the study of genetic programs and candidate pioneer factors in any developmental context. Finally, challenges and limitations intrinsic to the current next-generation sequencing techniques are discussed, as well as recent advances in super-resolution imaging, enabling spatio-temporal resolution of the genome.
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Malta, Tathiane, Thais Sabedot, Indrani Datta, Frederick Varn, AnaValeria Castro, Luciano Garofano, Roel Verhaak, Antonio Iavarone, Laila Poisson, and Houtan Noushmehr. "OTEH-10. Evolutionary trajectory of epigenomic of gliomas." Neuro-Oncology Advances 3, Supplement_2 (July 1, 2021): ii12. http://dx.doi.org/10.1093/noajnl/vdab070.049.
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Abstract Gliomas are the most common malignant brain tumor, have an aggressive behavior, and invariably relapse and progress. Despite the recent advancements, little is known about the role of the epigenome in glioma disease progression and recurrence. To investigate the molecular dynamics over time and in response to therapeutic pressures, the Glioma Longitudinal AnalySiS (GLASS) Consortium, a multinational collaboration, is investigating epigenome-wide molecular data from primary and recurrent matched pairs, including IDH mutant (IDHmut) and IDH wildtype (IDHwt) gliomas. We have compiled a total of 357 samples comprising 143 primary-recurrent pairs profiled by DNA methylation, of which 157 samples have genomic data (WXS/WGS) and 120 have transcriptomic data (RNAseq). IDHwt gliomas have a distinct epigenetic evolution compared to IDHmut after treatment. IDHwt gliomas are more epigenetically stable over time, while IDHmut gliomas display a loss of DNA methylation throughout disease progression. Next, we investigated the molecular drivers of longitudinal gliomas by integration of DNA methylation and gene expression data. We identified epigenetic activation of cell cycle pathways in recurrent IDHmut compared to initial tumors. Transcription factors musculin, ZNF367, and ZNF682 are enriched among recurrent IDHmut gliomas and potentially regulate IDHmut recurrence and/or progression. We next used a DNA methylation-based deconvolution approach to estimate the tumor microenvironment (TME) composition. We found that the TME among IDHmut subtypes (Codel, GCIMP-high, and GCIMP-low) presented less immune infiltration than IDHwt (Classic-like, Mesenchymal-like, and PA-like). Post-treatment, we found a decrease of CD4+T and an increase of CD8+T cells in IDHmut. In conclusion, IDHmut gliomas present a more unstable epigenome, while the epigenome of IDHwt gliomas seems relatively preserved after treatment. We identified potential master regulators of cell cycle deregulation of IDHmut recurrence. Finally, the TME differs across IDHmut and IDHwt gliomas and the cell composition changes over time.
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Duraisingh, Manoj T., and Kristen M. Skillman. "Epigenetic Variation and Regulation in Malaria Parasites." Annual Review of Microbiology 72, no. 1 (September 8, 2018): 355–75. http://dx.doi.org/10.1146/annurev-micro-090817-062722.
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Eukaryotic pathogens must survive in different hosts, respond to changing environments, and exploit specialized niches to propagate. Plasmodium parasites cause human malaria during bloodstream infections, where they must persist long enough to be transmitted. Parasites have evolved diverse strategies of variant gene expression that control critical biological processes of blood-stage infections, including antigenic variation, erythrocyte invasion, innate immune evasion, and nutrient acquisition, as well as life-cycle transitions. Epigenetic mechanisms within the parasite are being elucidated, with discovery of epigenomic marks associated with gene silencing and activation, and the identification of epigenetic regulators and chromatin proteins that are required for the switching and maintenance of gene expression. Here, we review the key epigenetic processes that facilitate transition through the parasite life cycle and epigenetic regulatory mechanisms utilized by Plasmodium parasites to survive changing environments and consider epigenetic switching in the context of the outcome of human infections.
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Wan, Chunhua, Sylvia Mahara, Claire Sun, Anh Doan, Hui Kheng Chua, Dakang Xu, Jia Bian, et al. "Genome-scale CRISPR-Cas9 screen of Wnt/β-catenin signaling identifies therapeutic targets for colorectal cancer." Science Advances 7, no. 21 (May 2021): eabf2567. http://dx.doi.org/10.1126/sciadv.abf2567.
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Aberrant activation of Wnt/β-catenin pathway is a key driver of colorectal cancer (CRC) growth and of great therapeutic importance. In this study, we performed comprehensive CRISPR screens to interrogate the regulatory network of Wnt/β-catenin signaling in CRC cells. We found marked discrepancies between the artificial TOP reporter activity and β-catenin–mediated endogenous transcription and redundant roles of T cell factor/lymphoid enhancer factor transcription factors in transducing β-catenin signaling. Compiled functional genomic screens and network analysis revealed unique epigenetic regulators of β-catenin transcriptional output, including the histone lysine methyltransferase 2A oncoprotein (KMT2A/Mll1). Using an integrative epigenomic and transcriptional profiling approach, we show that KMT2A loss diminishes the binding of β-catenin to consensus DNA motifs and the transcription of β-catenin targets in CRC. These results suggest that KMT2A may be a promising target for CRCs and highlight the broader potential for exploiting epigenetic modulation as a therapeutic strategy for β-catenin–driven malignancies.
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Zhang, Kai, Mengchi Wang, Ying Zhao, and Wei Wang. "Taiji: System-level identification of key transcription factors reveals transcriptional waves in mouse embryonic development." Science Advances 5, no. 3 (March 2019): eaav3262. http://dx.doi.org/10.1126/sciadv.aav3262.
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Transcriptional regulation is pivotal to the specification of distinct cell types during embryonic development. However, it still lacks a systematic way to identify key transcription factors (TFs) orchestrating the temporal and tissue specificity of gene expression. Here, we integrated epigenomic and transcriptomic data to reveal key regulators from two cells to postnatal day 0 in mouse embryogenesis. We predicted three-dimensional chromatin interactions in 12 tissues across eight developmental stages, which facilitates linking TFs to their target genes for constructing transcriptional regulatory networks. To identify driver TFs, we developed a new algorithm, dubbed Taiji, to assess the global influence of each TF and systematically uncovered TFs critical for lineage-specific and stage-dependent tissue specification. We have also identified TF combinations that function in spatiotemporal order to form transcriptional waves regulating developmental progress. Furthermore, lacking stage-specific TF combinations suggests a distributed timing strategy to orchestrate the coordination between tissues during embryonic development.
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Sun, Qian-Hui, Zi-Yu Kuang, Guang-Hui Zhu, Bao-Yi Ni, and Jie Li. "Multifaceted role of microRNAs in gastric cancer stem cells: Mechanisms and potential biomarkers." World Journal of Gastrointestinal Oncology 16, no. 2 (February 15, 2024): 300–313. http://dx.doi.org/10.4251/wjgo.v16.i2.300.
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MicroRNAs (miRNAs) have received much attention in the past decade as potential key epigenomic regulators of tumors and cancer stem cells (CSCs). The abnormal expression of miRNAs is responsible for different phenotypes of gastric cancer stem cells (GCSCs). Some specific miRNAs could be used as promising biomarkers and therapeutic targets for the identification of GCSCs. This review summarizes the coding process and biological functions of miRNAs and demonstrates their role and efficacy in gastric cancer (GC) metastasis, drug resistance, and apoptosis, especially in the regulatory mechanism of GCSCs. It shows that the overexpression of onco-miRNAs and silencing of tumor-suppressor miRNAs can play a role in promoting or inhibiting tumor metastasis, apart from the initial formation of GC. It also discusses the epigenetic regulation and potential clinical applications of miRNAs as well as the role of CSCs in the pathogenesis of GC. We believe that this review may help in designing novel therapeutic approaches for GC.
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Li, Cong-Jun, and Robert W. Li. "Bioinformatic Dissecting of TP53 Regulation Pathway Underlying Butyrate-induced Histone Modification in Epigenetic Regulation." Genetics & Epigenetics 6 (January 2014): GEG.S14176. http://dx.doi.org/10.4137/geg.s14176.
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Butyrate affects cell proliferation, differentiation, and motility. Butyrate inhibits histone deacetylase (HDAC) activities and induces cell-cycle arrest and apoptosis. TP53 is one of the most active upstream regulators discovered by ingenuity pathways analysis (IPA) in our RNA-sequencing data set. TP53 signaling pathway plays key role in many cellular processes. TP53 pathway and their involvement in cellular functions modified by butyrate treatment were scrutinized in this report by data mining the RNA-sequencing data using IPA (Ingenuity System®). The TP53 mechanistic pathway targets more than 600 genes. Downstream analysis predicted the activation of the TP53 pathway after butyrate treatment. The data mining also revealed that nine transcription factors are downstream regulators in TP53 signaling pathways. The analysis results also indicated that butyrate not only inhibits the HDAC activities, but also regulates genes encoding the HDAC enzymes through modification of histones and epigenomic landscape.
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Ayyamperumal, Parichitran, Hemant Chandru Naik, Amlan Jyoti Naskar, Lakshmi Sowjanya Bammidi, and Srimonta Gayen. "Epigenomic states contribute to coordinated allelic transcriptional bursting in iPSC reprogramming." Life Science Alliance 7, no. 4 (February 6, 2024): e202302337. http://dx.doi.org/10.26508/lsa.202302337.
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Two alleles of a gene can be transcribed independently or coordinatedly, which can lead to temporal expression heterogeneity with potentially distinct impacts on cell fate. Here, we profiled genome-wide allelic transcriptional burst kinetics during the reprogramming of MEF to induced pluripotent stem cells. We show that the degree of coordination of allelic bursting differs among genes, and alleles of many reprogramming-related genes burst in a highly coordinated fashion. Notably, we show that the chromatin accessibility of the two alleles of highly coordinated genes is similar, unlike the semi-coordinated or independent genes, suggesting the degree of coordination of allelic bursting is linked to allelic chromatin accessibility. Consistently, we show that many transcription factors have differential binding affinity between alleles of semi-coordinated or independent genes. We show that highly coordinated genes are enriched with chromatin accessibility regulators such as H3K4me3, H3K4me1, H3K36me3, H3K27ac, histone variant H3.3, and BRD4. Finally, we demonstrate that enhancer elements are highly enriched in highly coordinated genes. Our study demonstrates that epigenomic states contribute to coordinated allelic bursting to fine-tune gene expression during induced pluripotent stem cell reprogramming.
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Nam, Chehyun. "Abstract 4461: Unveiling the links between methionine metabolism and epigenomic reprogramming in upper aerodigestive squamous cell carcinoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4461. http://dx.doi.org/10.1158/1538-7445.am2024-4461.
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Abstract Upper aerodigestive squamous cell carcinoma (UASCC) presents as a prevalent and aggressive malignancy, posing challenges in terms of effective therapeutic interventions. In this study, we explored the intricacies of amino acid metabolism within UASCC, revealing an unexpected observation that distinguishes UASCC among all human cancers, having the highest methionine levels, driven by the overexpression of its transporter LAT1. Notably, LAT1 exhibits peak expression levels in UASCC, regulated at the transcriptional level by UASCC-specific promoters and enhancers, co-regulated by SCC master regulators TP63/KLF5/SREBF1.Surprisingly, our unbiased bioinformatic screen identifies EZH2 as a pivotal downstream target of the LAT1-methionine pathway, establishing a direct link between methionine metabolism and epigenomic reprogramming. This cascade emerges as crucial for the survival and proliferation of UASCC patient-derived tumor organoids. Furthermore, we find that LAT1 expression closely correlates with cellular sensitivity to inhibition of the LAT1-methionine-EZH2 axis.Significantly, the newly discovered LAT1-methionine-EZH2 cascade emerges as a promising target for intervention, with effective outcomes achievable through both pharmacological approaches and dietary interventions in vivo. In summary, this research unveils a novel mechanistic crosstalk connecting epigenomic reprogramming with methionine metabolism, revealing its biological significance in UASCC. Moreover, it identifies a unique tumor-specific vulnerability, providing avenues for exploitation through both pharmacological and dietary strategies Citation Format: Chehyun Nam. Unveiling the links between methionine metabolism and epigenomic reprogramming in upper aerodigestive squamous cell carcinoma [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 4461.
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McKinsey, Timothy A., Thomas M. Vondriska, and Yibin Wang. "Epigenomic regulation of heart failure: integrating histone marks, long noncoding RNAs, and chromatin architecture." F1000Research 7 (October 29, 2018): 1713. http://dx.doi.org/10.12688/f1000research.15797.1.
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Epigenetic processes are known to have powerful roles in organ development across biology. It has recently been found that some of the chromatin modulatory machinery essential for proper development plays a previously unappreciated role in the pathogenesis of cardiac disease in adults. Investigations using genetic and pharmacologic gain- and loss-of-function approaches have interrogated the function of distinct epigenetic regulators, while the increased deployment of the suite of next-generation sequencing technologies have fundamentally altered our understanding of the genomic targets of these chromatin modifiers. Here, we review recent developments in basic and translational research that have provided tantalizing clues that may be used to unlock the therapeutic potential of the epigenome in heart failure. Additionally, we provide a hypothesis to explain how signal-induced crosstalk between histone tail modifications and long non-coding RNAs triggers chromatin architectural remodeling and culminates in cardiac hypertrophy and fibrosis.
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Siu, Celia, Sam Wiseman, Sitanshu Gakkhar, Alireza Heravi-Moussavi, Misha Bilenky, Annaick Carles, Thomas Sierocinski, et al. "Characterization of the human thyroid epigenome." Journal of Endocrinology 235, no. 2 (November 2017): 153–65. http://dx.doi.org/10.1530/joe-17-0145.
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The thyroid gland, necessary for normal human growth and development, functions as an essential regulator of metabolism by the production and secretion of appropriate levels of thyroid hormone. However, assessment of abnormal thyroid function may be challenging suggesting a more fundamental understanding of normal function is needed. One way to characterize normal gland function is to study the epigenome and resulting transcriptome within its constituent cells. This study generates the first published reference epigenomes for human thyroid from four individuals using ChIP-seq and RNA-seq. We profiled six histone modifications (H3K4me1, H3K4me3, H3K27ac, H3K36me3, H3K9me3, H3K27me3), identified chromatin states using a hidden Markov model, produced a novel quantitative metric for model selection and established epigenomic maps of 19 chromatin states. We found that epigenetic features characterizing promoters and transcription elongation tend to be more consistent than regions characterizing enhancers or Polycomb-repressed regions and that epigenetically active genes consistent across all epigenomes tend to have higher expression than those not marked as epigenetically active in all epigenomes. We also identified a set of 18 genes epigenetically active and consistently expressed in the thyroid that are likely highly relevant to thyroid function. Altogether, these epigenomes represent a powerful resource to develop a deeper understanding of the underlying molecular biology of thyroid function and provide contextual information of thyroid and human epigenomic data for comparison and integration into future studies.
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Sobocińska, Joanna, Sara Molenda, Marta Machnik, and Urszula Oleksiewicz. "KRAB-ZFP Transcriptional Regulators Acting as Oncogenes and Tumor Suppressors: An Overview." International Journal of Molecular Sciences 22, no. 4 (February 23, 2021): 2212. http://dx.doi.org/10.3390/ijms22042212.
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Krüppel-associated box zinc finger proteins (KRAB-ZFPs) constitute the largest family of transcriptional factors exerting co-repressor functions in mammalian cells. In general, KRAB-ZFPs have a dual structure. They may bind to specific DNA sequences via zinc finger motifs and recruit a repressive complex through the KRAB domain. Such a complex mediates histone deacetylation, trimethylation of histone 3 at lysine 9 (H3K9me3), and subsequent heterochromatization. Nevertheless, apart from their repressive role, KRAB-ZFPs may also co-activate gene transcription, likely through interaction with other factors implicated in transcriptional control. KRAB-ZFPs play essential roles in various biological processes, including development, imprinting, retroelement silencing, and carcinogenesis. Cancer cells possess multiple genomic, epigenomic, and transcriptomic aberrations. A growing number of data indicates that the expression of many KRAB-ZFPs is altered in several tumor types, in which they may act as oncogenes or tumor suppressors. Hereby, we review the available literature describing the oncogenic and suppressive roles of various KRAB-ZFPs in cancer. We focused on their association with the clinicopathological features and treatment response, as well as their influence on the cancer cell phenotype. Moreover, we summarized the identified upstream and downstream molecular mechanisms that may govern the functioning of KRAB-ZFPs in a cancer setting.
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Yi, Mei, Yixin Tan, Li Wang, Jing Cai, Xiaoling Li, Zhaoyang Zeng, Wei Xiong, et al. "TP63 links chromatin remodeling and enhancer reprogramming to epidermal differentiation and squamous cell carcinoma development." Cellular and Molecular Life Sciences 77, no. 21 (May 23, 2020): 4325–46. http://dx.doi.org/10.1007/s00018-020-03539-2.
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Abstract Squamous cell carcinoma (SCC) is an aggressive malignancy that can originate from various organs. TP63 is a master regulator that plays an essential role in epidermal differentiation. It is also a lineage-dependent oncogene in SCC. ΔNp63α is the prominent isoform of TP63 expressed in epidermal cells and SCC, and overexpression promotes SCC development through a variety of mechanisms. Recently, ΔNp63α was highlighted to act as an epidermal-specific pioneer factor that binds closed chromatin and enhances chromatin accessibility at epidermal enhancers. ΔNp63α coordinates chromatin-remodeling enzymes to orchestrate the tissue-specific enhancer landscape and three-dimensional high-order architecture of chromatin. Moreover, ΔNp63α establishes squamous-like enhancer landscapes to drive oncogenic target expression during SCC development. Importantly, ΔNp63α acts as an upstream regulator of super enhancers to activate a number of oncogenic transcripts linked to poor prognosis in SCC. Mechanistically, ΔNp63α activates genes transcription through physically interacting with a number of epigenetic modulators to establish enhancers and enhance chromatin accessibility. In contrast, ΔNp63α also represses gene transcription via interacting with repressive epigenetic regulators. ΔNp63α expression is regulated at multiple levels, including transcriptional, post-transcriptional, and post-translational levels. In this review, we summarize recent advances of p63 in epigenomic and transcriptional control, as well as the mechanistic regulation of p63.
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El Zarif, Talal, Karl Semaan, Marc Eid, Brad Fortunato, Amin H. Nassar, Sarah Abou Alaiwi, Ziad Bakouny, et al. "Epigenomic profiling nominates master transcription factors (TFs) driving sarcomatoid differentiation (SD) of renal cell carcinoma (RCC)." Oncologist 28, Supplement_1 (August 23, 2023): S8. http://dx.doi.org/10.1093/oncolo/oyad216.012.
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Abstract Background Sarcomatoid differentiation of RCC (sRCC) is associated with poor survival. Recent studies showed marked response of sRCC to immune checkpoint blockade (ICB). While distinctive patterns of gene expression in sRCC have been identified, the gene regulatory programs and TFs that drive SD remain unknown. The aim of this study is to nominate TFs responsible for SD and to investigate their association with the clinical outcomes of patients with RCC. Methods Chromatin immunoprecipitation and sequencing (ChIP-seq) for H3K27ac – a histone modification associated with active regulatory elements – was performed on pathologically reviewed sRCC and non-sRCC samples collected at the Dana-Farber Cancer Institute. Regulatory elements that were differentially active between the two groups were identified based on levels of H3K27ac (Benjamini-Hochberg q<0.01, log-fold change (LFC) threshold=1). Enrichment of specific TF binding motifs at activated regulatory elements in sRCC was assessed using HOMER. Differential gene expression analysis of TFs was performed using DESeq2 on RNA-seq data from TCGA. A Mann-Whitney U test was performed on RNA-seq data from the IMmotion151 and Javelin Renal 101 clinical trials to compare mean expression level of TFs in transcript per million (TPM) in these trials. Patients with non-sRCC enrolled in the IMmotion151 trials were divided into quartiles based on gene expression levels of candidate TFs. Progression-free survival (PFS) was compared between non-sRCC patients stratified by expression quartiles as well as patients with sRCC using a multivariable Cox proportional-hazards model accounting for age and IMDC risk score. To validate these findings, a similar analysis was performed in the Javelin Renal 101 trial. Results We obtained high-quality H3K27ac ChIP-seq profiles for 9 sRCC and 17 non-sRCC samples. We identified 278 candidate regulatory elements with increased H3K27ac levels in sRCC vs. non-sRCC. These regulatory elements were enriched for nucleotide motifs bound by the TFs FOSL1 and E2F7. Differential expression analysis between 48 sRCC vs. 493 non-sRCC samples showed that FOSL1 and E2F7 were significantly upregulated in sRCC vs. non-sRCC (LFC=1.7, q=5e-11; LFC=1.8, q=1.3e-20; resp.). Mean TPMs of FOSL1 and E2F7 were significantly increased in sRCC vs. non-sRCC in IMmotion151 cohort and Javelin Renal 101 (all p<0.001). Among patients who received sunitinib, those with the highest quartile of FOSL1 and E2F7 expression showed significantly shorter PFS in IMmotion151 patients compared to patients with the lowest quartile of expression (HR=1.6, 95%CI=1.3-2.2, p=0.008 & HR=2.6, 95%CI=1.8-3.7, p<0.001; resp.). Furthermore, patients with highest quartile of expression showed similar PFS compared to patients with sRCC (p=0.56 and p=0.64; resp.). These results were validated in the sunitinib arm of the Javelin Renal 101 cohort (Figure). Figure: Kaplan-Meier curves of progression-free survival (PFS) in patients with in the sunitinib arm of Javelin Renal 101 by sarcomatoid differentiation and FOSL1 expression levels. Conclusions This is the first study to characterize the epigenomic landscape of sRCC by integrating ChIP-seq and RNA-seq data. Our findings implicated FOSL1 and E2F7 as transcriptional regulators of SD with prognostic relevance. These TFs seems to be associated with aggressive behavior in non-sRCC as well. Further studies are underway to functionally validate these results.
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Volpato, Viola. "Integration of functional genomics data to uncover cell type-specific pathways affected in Parkinson's disease." Biochemical Society Transactions 49, no. 5 (September 28, 2021): 2091–100. http://dx.doi.org/10.1042/bst20210128.
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Parkinson's disease (PD) is the second most prevalent late-onset neurodegenerative disorder worldwide after Alzheimer's disease for which available drugs only deliver temporary symptomatic relief. Loss of dopaminergic neurons (DaNs) in the substantia nigra and intracellular alpha-synuclein inclusions are the main hallmarks of the disease but the events that cause this degeneration remain uncertain. Despite cell types other than DaNs such as astrocytes, microglia and oligodendrocytes have been recently associated with the pathogenesis of PD, we still lack an in-depth characterisation of PD-affected brain regions at cell-type resolution that could help our understanding of the disease mechanisms. Nevertheless, publicly available large-scale brain-specific genomic, transcriptomic and epigenomic datasets can be further exploited to extract different layers of cell type-specific biological information for the reconstruction of cell type-specific transcriptional regulatory networks. By intersecting disease risk variants within the networks, it may be possible to study the functional role of these risk variants and their combined effects at cell type- and pathway levels, that, in turn, can facilitate the identification of key regulators involved in disease progression, which are often potential therapeutic targets.
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Durek, Pawel, Karl Nordström, Gilles Gasparoni, Abdulrahman Salhab, Christopher Kressler, Melanie de Almeida, Kevin Bassler, et al. "Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development." Immunity 45, no. 5 (November 2016): 1148–61. http://dx.doi.org/10.1016/j.immuni.2016.10.022.
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Loppin, Benjamin, and Frédéric Berger. "Histone Variants: The Nexus of Developmental Decisions and Epigenetic Memory." Annual Review of Genetics 54, no. 1 (November 23, 2020): 121–49. http://dx.doi.org/10.1146/annurev-genet-022620-100039.
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Nucleosome dynamics and properties are central to all forms of genomic activities. Among the core histones, H3 variants play a pivotal role in modulating nucleosome structure and function. Here, we focus on the impact of H3 variants on various facets of development. The deposition of the replicative H3 variant following DNA replication is essential for the transmission of the epigenomic information encoded in posttranscriptional modifications. Through this process, replicative H3 maintains cell fate while, in contrast, the replacement H3.3 variant opposes cell differentiation during early embryogenesis. In later steps of development, H3.3 and specialized H3 variants are emerging as new, important regulators of terminal cell differentiation, including neurons and gametes. The specific pathways that regulate the dynamics of the deposition of H3.3 are paramount during reprogramming events that drive zygotic activation and the initiation of a new cycle of development.
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Hersh, Andrew M., Hallie Gaitsch, Safwan Alomari, Daniel Lubelski, and Betty M. Tyler. "Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy." Cancers 14, no. 15 (July 31, 2022): 3743. http://dx.doi.org/10.3390/cancers14153743.
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Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival.
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Guo, Michael H., Satish K. Nandakumar, Jacob C. Ulirsch, Seyedeh M. Zekavat, Jason D. Buenrostro, Pradeep Natarajan, Rany M. Salem, et al. "Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms." Proceedings of the National Academy of Sciences 114, no. 3 (December 28, 2016): E327—E336. http://dx.doi.org/10.1073/pnas.1619052114.
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Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.
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Semaan, Karl, Talal El Zarif, Marc Eid, Valisha Shah, Brad Fortunato, Renee Maria Saliby, Amin H. Nassar, et al. "Abstract A029: Epigenomic profiling nominates master transcription factors (TFs) driving sarcomatoid differentiation of renal cell carcinoma (RCC)." Cancer Research 83, no. 16_Supplement (August 15, 2023): A029. http://dx.doi.org/10.1158/1538-7445.kidney23-a029.
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Abstract Introduction Sarcomatoid RCC (sRCC) is associated with poor prognosis. Recent studies showed promising response rates of sRCC to immune checkpoint blockade (ICB). Although distinct patterns of gene expression in sRCC have been reported, the gene regulatory programs that drive SD remain unknown. This study aims to nominate TFs driving SD and to evaluate their impact on the clinical outcomes of patients (pts) with RCC. Methods Chromatin immunoprecipitation and sequencing (ChIP-seq) for H3K27ac was performed on histologically annotated areas of sRCC and non-sRCC fresh frozen tissue samples collected at Dana-Farber Cancer Institute. Regulatory elements that were differentially active between the two groups were identified (cutoff p<0.01, log-fold change (LFC) threshold=1). Enrichment of specific TF binding motifs at activated regulatory elements in sRCC was assessed using HOMER. Differential gene expression analysis of TFs was performed using DESeq2 on RNA-seq data from TCGA (Benjamini-Hochberg q <0.01, LFC threshold=1). An unpaired student’s t-test was performed to compare mean gene expression levels in transcript per million (TPM) on baseline sRCC and non-sRCC tissue samples from the IMmotion151 trial (sunitinib vs. atezolizumab-bevacizumab in metastatic RCC). Pts enrolled in the IMmotion151 trial were divided into quartiles based on gene expression levels of candidate TFs. Progression-free survival (PFS) was compared between the quartiles using a multivariable Cox proportional-hazards model accounting for age and IMDC risk score. The association of TF expression with the objective radiographic response (ORR) was analyzed using a logistic regression model. Results ChIP-seq was performed on 9 sRCC & 17 non-sRCC samples. We identified 278 candidate regulatory elements with increased H3K27ac levels in sRCC vs. non-sRCC that were enriched for nucleotide motifs bound by the TFs FOSL1 and E2F7. Differential expression analysis between 48 sRCC vs. 493 non-sRCC samples showed that FOSL1 & E2F7 were significantly upregulated in sRCC vs. non-sRCC (LFC=1.7, q=5e-11; LFC=1.8, q=1.3e-20; resp.). Mean TPMs of FOSL1 & E2F7 were significantly increased in sRCC vs. non-sRCC in IMmotion151 cohort (2.5 vs. 1.5 TPM for FOSL1, and 2.9 vs. 1.9 TPM for E2F7, all p<0.001). Pts in the highest quartile of FOSL1 and E2F7 expression showed significantly shorter PFS in IMmotion151 pts receiving sunitinib alone (HR=1.6, 95%CI=1.3-2.2, p=0.008 & HR=2.6, 95%CI=1.8-3.7, p<0.001; resp.). We observed similar results even after controlling for the presence of SD. Increased expression of E2F7 was associated with worse ORR in IMmotion151 pts who received sunitinib alone, even after controlling for the presence of SD (OR=0.24±0.4, p<0.001). Conclusion This is the first study to analyze the epigenomic landscape of sRCC by integrating ChIP-seq and RNA-seq data. Our findings implicated FOSL1 & E2F7 as transcriptional regulators of SD with prognostic relevance. Further studies are underway to validate these results. Citation Format: Karl Semaan, Talal El Zarif, Marc Eid, Valisha Shah, Brad Fortunato, Renee Maria Saliby, Amin H. Nassar, Sarah Abou Alaiwi, Ji-Heui Seo, Chris Labaki, Ziad Bakouny, Sayed Matar, Nourhan El Ahmar, Yasmin Nabil Laimon, Gwo-Shu Mary Lee, Mark Pomerantz, Jacob Berchuck, Sabina Signoretti, Eliezer Van Allen, Toni Choueiri, David Braun, Matthew Freedman, Sylvan Baca. Epigenomic profiling nominates master transcription factors (TFs) driving sarcomatoid differentiation of renal cell carcinoma (RCC) [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A029.
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Enfield, Katey S. S., Larissa A. Pikor, Victor D. Martinez, and Wan L. Lam. "Mechanistic Roles of Noncoding RNAs in Lung Cancer Biology and Their Clinical Implications." Genetics Research International 2012 (July 18, 2012): 1–16. http://dx.doi.org/10.1155/2012/737416.
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Lung cancer biology has traditionally focused on genomic and epigenomic deregulation of protein-coding genes to identify oncogenes and tumor suppressors diagnostic and therapeutic targets. Another important layer of cancer biology has emerged in the form of noncoding RNAs (ncRNAs), which are major regulators of key cellular processes such as proliferation, RNA splicing, gene regulation, and apoptosis. In the past decade, microRNAs (miRNAs) have moved to the forefront of ncRNA cancer research, while the role of long noncoding RNAs (lncRNAs) is emerging. Here we review the mechanisms by which miRNAs and lncRNAs are deregulated in lung cancer, the technologies that can be applied to detect such alterations, and the clinical potential of these RNA species. An improved comprehension of lung cancer biology will come through the understanding of the interplay between deregulation of non-coding RNAs, the protein-coding genes they regulate, and how these interactions influence cellular networks and signalling pathways.
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Sato, Takashi, Junko Hamamoto, Katsura Emoto, Takahiro Fukushima, Kai Sugihara, Masayuki Shirasawa, Yoshiro Nakahara, et al. "Abstract 5715: Epigenomic profiling identifies distinct neuroendocrine subtypes in lung cancer with neuroendocrine differentiation." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5715. http://dx.doi.org/10.1158/1538-7445.am2022-5715.
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Abstract Lung cancer is the leading cause of cancer-related death worldwide, among which high-grade neuroendocrine tumors including small-cell lung cancer (SCLC) and pulmonary large-cell neuroendocrine carcinoma (LCNEC) are especially aggressive with a dismal prognosis. Although molecular subtypes of SCLC based on the expression of lineage transcription factors such as ASCL1, NEUROD1, POU2F3 and YAP1 have been identified and explored recently, LCNEC has not been well characterized so far, and in clinic, patients with LCNEC have been treated with both chemotherapy regimens for SCLC and regimens for non-small cell lung cancer. To make efficient treatment strategies for LCNEC, further advances in molecular characterization of LCNEC are warranted. Therefore, in this study, we aimed to elucidate the heterogeneity of neuroendocrine differentiation in lung cancer with LCNEC components by using epigenomic profiling. We investigated super-enhancer profiles of 24 formalin-fixed paraffin-embedded tumor tissues from patients with primary lung cancer containing LCNEC components. Unsupervised hierarchical clustering of these specimens using H3K27 acetylation signals over super-enhancer regions near transcriptional regulators identified four distinct clusters. Principal component analysis supported this classification. Immunohistochemical staining for ASCL1, NEUROD1, POU2F3 and YAP1 on these tissues was also performed and the staining results were compatible with our epigenomic profiling. Cluster 1 tissues were positive for ASCL1 and NKX2-1 while the high expression of POU2F3 or YAP1 was found in some samples among Cluster 3 and Cluster 4. None of the four transcription factors were positive in Cluster 2. Additional genomic profiling revealed no clear associations between the clusters and genetic alterations such as RB1 loss and STK11 loss. Neuroendocrine markers synaptophysin, chromogranin A and CD56 were found to be more commonly positive in tissues among Cluster 1. These findings suggest the existence of the distinct differentiation subtypes of lung cancer with LCNEC components, different from the previously reported classifications, which provides new insight into the regulation of neuroendocrine differentiation in lung cancer. Citation Format: Takashi Sato, Junko Hamamoto, Katsura Emoto, Takahiro Fukushima, Kai Sugihara, Masayuki Shirasawa, Yoshiro Nakahara, Satoshi Igawa, Yoshiki Murakumo, Takashi Kohno, Kouya Shiraishi, Hiroyuki Yasuda, Kenzo Soejima, Hideo Watanabe, Katsuhiko Naoki. Epigenomic profiling identifies distinct neuroendocrine subtypes in lung cancer with neuroendocrine differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5715.
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Schmitz, Robert J., Alexandre P. Marand, Xuan Zhang, Rebecca A. Mosher, Franziska Turck, Xuemei Chen, Michael J. Axtell, et al. "Quality control and evaluation of plant epigenomics data." Plant Cell 34, no. 1 (October 14, 2021): 503–13. http://dx.doi.org/10.1093/plcell/koab255.
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Abstract Epigenomics is the study of molecular signatures associated with discrete regions within genomes, many of which are important for a wide range of nuclear processes. The ability to profile the epigenomic landscape associated with genes, repetitive regions, transposons, transcription, differential expression, cis-regulatory elements, and 3D chromatin interactions has vastly improved our understanding of plant genomes. However, many epigenomic and single-cell genomic assays are challenging to perform in plants, leading to a wide range of data quality issues; thus, the data require rigorous evaluation prior to downstream analyses and interpretation. In this commentary, we provide considerations for the evaluation of plant epigenomics and single-cell genomics data quality with the aim of improving the quality and utility of studies using those data across diverse plant species.
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Richard, Gautier, Julie Jaquiéry, and Gaël Le Trionnaire. "Contribution of Epigenetic Mechanisms in the Regulation of Environmentally-Induced Polyphenism in Insects." Insects 12, no. 7 (July 15, 2021): 649. http://dx.doi.org/10.3390/insects12070649.
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Many insect species display a remarkable ability to produce discrete phenotypes in response to changes in environmental conditions. Such phenotypic plasticity is referred to as polyphenism. Seasonal, dispersal and caste polyphenisms correspond to the most-studied examples that are environmentally-induced in insects. Cues that induce such dramatic phenotypic changes are very diverse, ranging from seasonal cues, habitat quality changes or differential larval nutrition. Once these signals are perceived, they are transduced by the neuroendocrine system towards their target tissues where gene expression reprogramming underlying phenotypic changes occur. Epigenetic mechanisms are key regulators that allow for genome expression plasticity associated with such developmental switches. These mechanisms include DNA methylation, chromatin remodelling and histone post-transcriptional modifications (PTMs) as well as non-coding RNAs and have been studied to various extents in insect polyphenism. Differential patterns of DNA methylation between phenotypes are usually correlated with changes in gene expression and alternative splicing events, especially in the cases of dispersal and caste polyphenism. Combinatorial patterns of histone PTMs provide phenotype-specific epigenomic landscape associated with the expression of specific transcriptional programs, as revealed during caste determination in honeybees and ants. Alternative phenotypes are also usually associated with specific non-coding RNA profiles. This review will provide a summary of the current knowledge of the epigenetic changes associated with polyphenism in insects and highlights the potential for these mechanisms to be key regulators of developmental transitions triggered by environmental cues.
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Wulfridge, Phillip, Adam Davidovich, Anna C. Salvador, Gabrielle C. Manno, Rakel Tryggvadottir, Adrian Idrizi, M. Nazmul Huda, et al. "Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation." PLOS Genetics 19, no. 10 (October 23, 2023): e1010997. http://dx.doi.org/10.1371/journal.pgen.1010997.
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Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the Farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach.
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Yamagishi, Makoto. "The role of epigenetics in T-cell lymphoma." International Journal of Hematology, October 14, 2022. http://dx.doi.org/10.1007/s12185-022-03470-1.
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AbstractMalignant lymphomas are a group of diseases with epigenomic abnormalities fundamental to pathogenesis and pathophysiology. They are characterized by a high frequency of abnormalities related to DNA methylation regulators (DNMT3A, TET2, IDH2, etc.) and histone modifiers (EZH2, HDAC, KMT2D/MLL2, CREBBP, EP300, etc.). These epigenomic abnormalities directly amplify malignant clones. They also originate from a hematopoietic stem cell-derived cell lineage triggered by epigenomic changes. These characteristics are linked to their high affinity for epigenomic therapies. Hematology has led disease epigenetics in the areas of basic research, clinical research, and drug discovery. However, epigenomic regulation is generally recognized as a complex system, and gaps exist between basic and clinical research. To provide an overview of the status and importance of epigenomic abnormalities in malignant lymphoma, this review first summarizes the concept and essential importance of the epigenome, then outlines the current status and future outlook of epigenomic abnormalities in malignant lymphomas.
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Bell, Christopher G. "Epigenomic insights into common human disease pathology." Cellular and Molecular Life Sciences 81, no. 1 (April 11, 2024). http://dx.doi.org/10.1007/s00018-024-05206-2.
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AbstractThe epigenome—the chemical modifications and chromatin-related packaging of the genome—enables the same genetic template to be activated or repressed in different cellular settings. This multi-layered mechanism facilitates cell-type specific function by setting the local sequence and 3D interactive activity level. Gene transcription is further modulated through the interplay with transcription factors and co-regulators. The human body requires this epigenomic apparatus to be precisely installed throughout development and then adequately maintained during the lifespan. The causal role of the epigenome in human pathology, beyond imprinting disorders and specific tumour suppressor genes, was further brought into the spotlight by large-scale sequencing projects identifying that mutations in epigenomic machinery genes could be critical drivers in both cancer and developmental disorders. Abrogation of this cellular mechanism is providing new molecular insights into pathogenesis. However, deciphering the full breadth and implications of these epigenomic changes remains challenging. Knowledge is accruing regarding disease mechanisms and clinical biomarkers, through pathogenically relevant and surrogate tissue analyses, respectively. Advances include consortia generated cell-type specific reference epigenomes, high-throughput DNA methylome association studies, as well as insights into ageing-related diseases from biological ‘clocks’ constructed by machine learning algorithms. Also, 3rd-generation sequencing is beginning to disentangle the complexity of genetic and DNA modification haplotypes. Cell-free DNA methylation as a cancer biomarker has clear clinical utility and further potential to assess organ damage across many disorders. Finally, molecular understanding of disease aetiology brings with it the opportunity for exact therapeutic alteration of the epigenome through CRISPR-activation or inhibition.
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Henaff, Carole Le, Nicola Partridge, Frederic Jehan, and Valerie Geoffroy. "Identification of epigenomic regulators of osteoblast function." Bone Abstracts, April 21, 2016. http://dx.doi.org/10.1530/boneabs.5.p249.
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Lee, Ji-Eun, Hannah Schmidt, Binbin Lai, and Kai Ge. "Transcriptional and Epigenomic Regulation of Adipogenesis." Molecular and Cellular Biology 39, no. 11 (April 1, 2019). http://dx.doi.org/10.1128/mcb.00601-18.
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ABSTRACT Understanding adipogenesis, the process of adipocyte development, may provide new ways to treat obesity and related metabolic diseases. Adipogenesis is controlled by coordinated actions of lineage-determining transcription factors and epigenomic regulators. Peroxisome proliferator-activated receptor gamma (PPARγ) and C/EBPα are master “adipogenic” transcription factors. In recent years, a growing number of studies have reported the identification of novel transcriptional and epigenomic regulators of adipogenesis. However, many of these novel regulators have not been validated in adipocyte development in vivo and their working mechanisms are often far from clear. In this minireview, we discuss recent advances in transcriptional and epigenomic regulation of adipogenesis, with a focus on factors and mechanisms shared by both white adipogenesis and brown adipogenesis. Studies on the transcriptional regulation of adipogenesis highlight the importance of investigating adipocyte differentiation in vivo rather than drawing conclusions based on knockdown experiments in cell culture. Advances in understanding of epigenomic regulation of adipogenesis have revealed critical roles of histone methylation/demethylation, histone acetylation/deacetylation, chromatin remodeling, DNA methylation, and microRNAs in adipocyte differentiation. We also discuss future research directions that may help identify novel factors and mechanisms regulating adipogenesis.