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Baronchelli, Simona, Angela Bentivegna, Serena Redaelli, Gabriele Riva, Valentina Butta, Laura Paoletta, Giuseppe Isimbaldi, et al. "Delineating the Cytogenomic and Epigenomic Landscapes of Glioma Stem Cell Lines." PLoS ONE 8, no. 2 (February 28, 2013): e57462. http://dx.doi.org/10.1371/journal.pone.0057462.
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Redaelli, Serena, Angela Bentivegna, Dana Foudah, Mariarosaria Miloso, Juliana Redondo, Gabriele Riva, Simona Baronchelli, Leda Dalpra, and Giovanni Tredici. "From cytogenomic to epigenomic profiles: monitoring the biological behavior of in vitro cultured human bone marrow mesenchymal stem cells." Stem Cell Research & Therapy 3, no. 6 (2012): 47. http://dx.doi.org/10.1186/scrt138.
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Mathur, Radhika, Qixuan Wang, Patrick Schupp, Stephanie Hilz, Chibo Hong, Ivan Smirnov, Marisa Lafontaine, et al. "ECOA-5. Integrative 3D spatial characterization of genomic and epigenomic intratumoral heterogeneity in glioblastoma." Neuro-Oncology Advances 3, Supplement_2 (July 1, 2021): ii2. http://dx.doi.org/10.1093/noajnl/vdab070.005.
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Abstract Treatment failure in glioblastoma is often attributed to intratumoral heterogeneity (ITH), which fosters tumor evolution and selection of therapy-resistant clones. While genomic alterations are known contributors to ITH, emerging studies highlight functional roles for epigenomic ITH which integrates differentiation status, stochastic events, and microenvironmental inputs. Here, we have established a novel platform for integrative characterization of genomic and epigenomic ITH of glioblastoma in three-dimensional (3-D) space. In collaboration with neurosurgeons and biomedical imaging experts, we utilize 3-D surgical neuro-navigation to safely acquire ~10 tumor samples per patient representing maximal anatomical diversity. We conduct whole-exome sequencing, RNA sequencing, and assay for transposase-accessible chromatin using sequencing (ATAC-Seq) on each sample. The spatial location of each sample is mapped by its 3-D coordinates, allowing 360-degree visualization of genomic and epigenomic ITH for each patient. We demonstrate this approach on 8 patients with primary IDH-WT glioblastoma (83 spatially mapped samples), providing unprecedented insight into their spatial organization at the genomic and epigenomic levels. We link genetically defined tumor subclones to patterns of open chromatin and gene regulation, revealing underlying transcription factor binding at active promoters and enhancers. We also identify ITH in whole-genome doubling and focal oncogene amplification events in multiple patients, which we then link with epigenomic ITH. Further, to study microenvironmental inputs and their contribution to epigenomic ITH, we conduct deconvolution of RNA sequencing and ATAC-Seq data by analyzing feature co-variation. We resolve the 3-D spatial organization of immune, neural, and other nontumor cell types present in glioblastoma, characterizing their functional states and interactions with tumor cells. This work provides the most comprehensive spatial characterization of genomic and epigenomic ITH to date in glioblastoma. As a resource for further investigation, we have developed an interactive data sharing platform – The 3D Glioma Atlas – that enables 360-degree visualization of both genomic and epigenomic ITH.
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Siegel, Erin M., Steven Eschrich, Kathryn Winter, Bridget Riggs, Anders Berglund, Abidemi Ajidahun, Jeff Simko, et al. "Epigenomic Characterization of Locally Advanced Anal Cancer." Diseases of the Colon & Rectum 57, no. 8 (August 2014): 941–57. http://dx.doi.org/10.1097/dcr.0000000000000160.
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Sahajpal, Nikhil, Ashis Mondal, Suzanne Hurley, Alex Hastie, Alka Chaubey, Amyn Rojiani, Fariborz Rashid-Kolvear, and Ravindra Kolhe. "Next-generation cytogenomic characterization of prenatal cases by Optical Genome Mapping." Molecular Genetics and Metabolism 132 (April 2021): S322. http://dx.doi.org/10.1016/s1096-7192(21)00580-1.
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Roxo, Guilherme, Mónica Moura, Pedro Talhinhas, José Carlos Costa, Luís Silva, Raquel Vasconcelos, Miguel Menezes de Sequeira, and Maria Manuel Romeiras. "Diversity and Cytogenomic Characterization of Wild Carrots in the Macaronesian Islands." Plants 10, no. 9 (September 18, 2021): 1954. http://dx.doi.org/10.3390/plants10091954.
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The Macaronesian islands constitute an enormous reservoir of genetic variation of wild carrots (subtribe Daucinae; Apiaceae), including 10 endemic species, but an accurate understanding of the diversification processes within these islands is still lacking. We conducted a review of the morphology, ecology, and conservation status of the Daucinae species and, on the basis of a comprehensive dataset, we estimated the genome size variation for 16 taxa (around 320 samples) occurring in different habitats across the Macaronesian islands in comparison to mainland specimens. Results showed that taxa with larger genomes (e.g., Daucus crinitus: 2.544 pg) were generally found in mainland regions, while the insular endemic taxa from Azores and Cabo Verde have smaller genomes. Melanoselinum decipiens and Monizia edulis, both endemic to Madeira Island, showed intermediate values. Positive correlations were found between mean genome size and some morphological traits (e.g., spiny or winged fruits) and also with habit (herbaceous or woody). Despite the great morphological variation found within the Cabo Verde endemic species, the 2C-values obtained were quite homogeneous between these taxa and the subspecies of Daucus carota, supporting the close relationship among these taxa. Overall, this study improved the global knowledge of DNA content for Macaronesian endemics and shed light into the mechanisms underpinning diversity patterns of wild carrots in the western Mediterranean region.
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Azawi, Shaymaa, Stefanie Kankel, Thomas Liehr, and Martina Rincic. "First cytogenomic characterization of murine testis tumor cell line MLTC-1." Molecular and experimental biology in medicine 4, no. 1 (December 16, 2022): 10–14. http://dx.doi.org/10.33602/mebm.4.1.2.
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The cell line MLTC-1 was established in 1982 as a transplantable Leydig cell tumor from a C57BL/6 mouse. The cell line has already been applied in >100 studies: still, the only information about its genetic content is given in the first description: MLTC-1 initially had a polyploid karyotype. Here, a molecular karyotyping and multicolor banding-based molecular cytogenetic study was done to provide the first chromosomal/ (molecular) cytogenetic characterization of MLTC-1. A hexaploid karyotype with 72 to 105 chromosomes was hereby characterized. Besides polyploidy, unbalanced two- and three-way translocations, dicentrics and one neocentric derivative were identified. Also, no Y-chromosome could be detected in this clearly male derived cell line. Overall, a completely unbalanced genome is present in MLTC-1 with ~20 regions being subject to copy number losses or gains. After translating these imbalances into the human genome in a standardized way, a 40% match of imbalances with human Leydig cell tumors was evident; however, about the same rate of concordance was detectable for human spermatocytic seminomas and non-seminomas as well as testicular germ cell tumor. Accordingly, MLTC-1 is better suited as an advanced testicular germ cell tumor model in general, rather than specifically for human Leydig cell tumors.
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Nam, Chehyun, Benjamin Ziman, Megha Sheth, Hua Zhao, and De-Chen Lin. "Genomic and Epigenomic Characterization of Tumor Organoid Models." Cancers 14, no. 17 (August 24, 2022): 4090. http://dx.doi.org/10.3390/cancers14174090.
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Tumor organoid modeling has been recognized as a state-of-the-art system for in vitro research on cancer biology and precision oncology. Organoid culture technologies offer distinctive advantages, including faithful maintenance of physiological and pathological characteristics of human disease, self-organization into three-dimensional multicellular structures, and preservation of genomic and epigenomic landscapes of the originating tumor. These features effectively position organoid modeling between traditional cell line cultures in two dimensions and in vivo animal models as a valid, versatile, and robust system for cancer research. Here, we review recent advances in genomic and epigenomic characterization of tumor organoids and the novel findings obtained, highlight significant progressions achieved in organoid modeling of gene–drug interactions and genotype–phenotype associations, and offer perspectives on future opportunities for organoid modeling in basic and clinical cancer research.
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Graff-Baker, Amanda N., Javier I. J. Orozco, Diego M. Marzese, Matthew P. Salomon, Dave S. B. Hoon, and Melanie Goldfarb. "Epigenomic and Transcriptomic Characterization of Secondary Breast Cancers." Annals of Surgical Oncology 25, no. 10 (June 28, 2018): 3082–87. http://dx.doi.org/10.1245/s10434-018-6582-7.
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Rodríguez Paredes, M., L. Solé Boldo, G. Raddatz, J. Gutekunst, M. Liberio, J. Mallm, K. Rippe, A. S. Lonsdorf, and F. Lyko. "469 Epigenomic characterization of non-melanoma skin cancer." Journal of Investigative Dermatology 139, no. 9 (September 2019): S295. http://dx.doi.org/10.1016/j.jid.2019.07.519.
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Koduru, Prasad, Weina Chen, Barbara Haley, Kevin Ho, Dwight Oliver, and Kathleen Wilson. "Cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia." Cancer Genetics 238 (October 2019): 69–75. http://dx.doi.org/10.1016/j.cancergen.2019.08.001.
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Ozenberger, Benjamin B., Li Li, and Kevin B. Jones. "Abstract 2356: The epigenomic characterization of clear cell sarcoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2356. http://dx.doi.org/10.1158/1538-7445.am2022-2356.
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Abstract Clear cell sarcoma (CCS) is an aggressive malignancy that affects adolescents and young adults. CCS is a translocation-driven sarcoma subtype meaning a genetic fusion event defines and drives the malignancy. The chromosomal translocation occurring between EWSR1 on chromosome 22 and ATF1 on chromosome 12 results in the EWSR1-ATF1 fusion oncogene (hereafter abbreviated EA1) which drives more than 90% of CCS cases. The EA1 oncoprotein is a transcription factor that reprograms gene expression to drive CCS. However, the target genes of EA1 and how EA1 affects target gene expression levels are largely unknown. Elucidation of these effectors is critical in order to understand how the EA1 oncoprotein drives the epigenetic reprogramming in CCS. We utilized a robust mouse model that recapitulates CCS in which mice express TATCre-inducible EA1. Using CCS tumors that form in these mice, ChIP-sequencing identified where EA1 is binding along the genome. Analysis in combination with RNA-sequencing data revealed target genes that are bound by EA1 and either upregulated or downregulated compared to control tissue. Target gene expression levels were corroborated in a human context by RNA-sequencing of human tumors and a CCS human cell line. RNAi knockdown of EA1 in the human cell line confirmed functionality of the fusion protein at these target genes. We show that EA1 can bind at promoter regions to directly regulate transcription of target genes. These binding sites include the canonical ATF binding motif. The EA1 target genes overlap with known wildtype ATF1 target genes. Many upregulated genes are involved in cell cycle and proliferation as expected. Alternatively, EA1 can bind intergenic regions including H3K27ac-defined super enhancers to distally regulate target genes. These binding sites contain unique DNA motifs that are different from the canonical ATF binding motif by 1 base pair. One highly recurrent motif identified matches the motif of the AP1 complex, a putative co-factor that may be functioning with EA1. These so-called variant motifs appear to define enhancer regions where EA1 can bind along with AP1. In summary, EA1 binds the expected ATF motif at promoter regions to directly regulate target gene expression. Secondly, EA1 binds intergenic enhancer regions defined by variant motifs including the AP1 motif. Target genes can either be upregulated or downregulated by the fusion, suggesting that there are secondary epigenetic mechanisms. One such model involves differential co-factor composition, such as AP1 co-binding, that dictates where EA1 binds or subsequent transcriptional effects. This research sets up the foundation for how EA1 functions as a transcription factor including the distribution of EA1 across the genome, the motifs that EA1 binds, and the key genes that are regulated by EA1. These epigenetic findings are crucial to understanding how a powerful fusion oncoprotein drives this aggressive, under-studied malignancy. Citation Format: Benjamin B. Ozenberger, Li Li, Kevin B. Jones. The epigenomic characterization of clear cell sarcoma [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 2356.
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Eckalbar, Walter L., Stephen A. Schlebusch, Mandy K. Mason, Zoe Gill, Ash V. Parker, Betty M. Booker, Sierra Nishizaki, et al. "Transcriptomic and epigenomic characterization of the developing bat wing." Nature Genetics 48, no. 5 (March 28, 2016): 528–36. http://dx.doi.org/10.1038/ng.3537.
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Sawalha, Amr H., and Mikhail G. Dozmorov. "Epigenomic functional characterization of genetic susceptibility variants in systemic vasculitis." Journal of Autoimmunity 67 (February 2016): 76–81. http://dx.doi.org/10.1016/j.jaut.2015.10.002.
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Yang, Hui, Guillermo Garcia-Manero, Guillermo Montalban-Bravo, Kelly S. Chien, Awdesh Kalia, Zhenya Tang, Yue Wei, et al. "High-Throughput Characterization of Cytogenomic Heterogeneity of MDS Using High-Resolution Optical Genome Mapping." Blood 138, Supplement 1 (November 5, 2021): 105. http://dx.doi.org/10.1182/blood-2021-154005.
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Abstract Introduction Introduction of next-generation sequencing has defined the somatic mutational landscape in MDS. Comprehensive high-throughput structural variant profiling (SVP) is as important as mutation profiling in characterizing MDS clonal architecture since these large genomic aberrations have already shown to be critical for diagnosis and risk-stratification of MDS. A subset (MECOM, KMT2A rearrangements) are therapeutic targets in clinical trials. At this time, technical advances in SVP for copy number alterations (CNAs) and fusions have not been congruent with mutation profiling due to the inability of short-read (150bp) NGS to detect SVs. Currently available long-read (10-20Kbp) and whole genome sequencing cannot detect all SVs due to the presence of repeat sequences. Hence, conventional karyotyping (CK) remains the gold standard. Optical genome mapping (OGM) is a novel single-platform technique that measures ultra-long-range sequence patterns (>300Kbp), thereby unaffected by repeat sequences, enabling unbiased evaluation of all types of SVs at a high resolution. Here, we performed comprehensive SVP and mutation profiling in a large well-characterized cohort of MDS. Methods We selected samples with available fresh/frozen BM cells from consecutive treatment-naïve MDS pts who also underwent standard-of-care tests (CK, FISH, targeted 81-gene NGS for mutations). For OGM, ultra-high-molecular-weight-DNA was extracted, followed by labeling, linearization and imaging of DNA (Saphyr, Bionano) [median coverage:>300X]. The results were analyzed using de novo (>500 bp), rare variant (>5000 bp) and copy number (>500,000 bp) pipelines. The data was compared against 200 healthy controls to exclude common germline SVs. Clinical significance of the SVs was determined based on the location/overlap with the coding region of myeloid malignancy associated genes. The detection sensitivity was 10%. Results There were 76 treatment naïve MDS patients. Baseline characteristics, comprehensive cytogenetic scoring system (CCSS) and R-IPPS risk categories and somatic mutations are in Fig 1. OGM identified all clonal abnormalities detected by CK [CNAs, inversions, inter/intra-chromosomal translocations, dicentric, complex derivative chromosomes]. Precise mapping of SVs by OGM at gene-level allowed determining the status of clinically informative biomarkers such as TET2, MECOM, TP53 and KMT2A, without the need for confirmatory assays. Detailed gene-level characterization of different SVs included KMT2A-ELL [t(11;19)] in MDS with WT1 mut, t(9;11) with SYTL2 fusion (and not KMT2A), der(1;7) leading to del(7q) in MDS with GATA2 mut/IDH2 mutand t(1;3)(p36;q21) rearrangements with potential PRDM16 disruption in SF3B1 mut/RUNX1 mutMDS, among others. Using OGM, we mapped the sequence patterns in both samples with IM with high level of confidence. Additionally, OGM identified 23 cryptic, clinically significant SVs in 14 (18%) of 76 pts. These included deletions of TET2, KMT2A, and del(5q), KMT2A amplification in MDS with FLT3-ITD/DNMT3A mut/RAS mut, NUP98-PRRX2, MECOM rearrangement in TET mut mutated NK-MDS. In addition, there were SVs of uncertain significance: duplications of chr1 (PDE41P), deletions of chr21 (involving RUNX1), chr2 (DNMT3A, ASXL2), chr12 (ETV6) and chr22 (EP300) and der(16)t(12;16)(q21.1;q12.1). These cryptic SVs were noted across all R-IPSS risk categories (highest yield in very-low and low R-IPSS) and across all cytogenetic risk-groups (very-good to very-poor). In complex karyotype setting, OGM could resolve the markers and additional genetic material, and in most cases, showed a much higher the degree of complexity within the genome than was apparent by CK. Four pts showed SV patterns typical of chromothripsis/chromoplexy. The median number of mutations per pt was 1 (0-6). When compared to mutation subsets, cryptic SVs were only identified in pts with ≤3 mutations. Majority represented either MDS with TP53 mut (6, 29%) or SF3B1 mut/TET mut (deletions of TET2, KMT2A, NOTCH1 and EP300 genes). Conclusions Unbiased, high-throughput whole genome SVP revealed cryptic, clinically significant SVs in ~18% of MDS pts. OGM is a single-platform cytogenomic tool that can facilitate SVP at a gene-level resolution. This study provides strong support for further validation in expanded cohorts to guide clinical implementation and integration of SVP for routine work-up. Figure 1 Figure 1. Disclosures Wei: Daiichi Sanko: Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria; Astra Zeneca: Honoraria; AbbVie: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Ascentage: Research Funding; Aptitude Health: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria.
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Viswanathan, Ramya, Elsie Cheruba, and Lih Feng Cheow. "DNA Analysis by Restriction Enzyme (DARE) enables concurrent genomic and epigenomic characterization of single cells." Nucleic Acids Research 47, no. 19 (August 16, 2019): e122-e122. http://dx.doi.org/10.1093/nar/gkz717.
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Abstract Genome-wide profiling of copy number alterations and DNA methylation in single cells could enable detailed investigation into the genomic and epigenomic heterogeneity of complex cell populations. However, current methods to do this require complex sample processing and cleanup steps, lack consistency, or are biased in their genomic representation. Here, we describe a novel single-tube enzymatic method, DNA Analysis by Restriction Enzyme (DARE), to perform deterministic whole genome amplification while preserving DNA methylation information. This method was evaluated on low amounts of DNA and single cells, and provides accurate copy number aberration calling and representative DNA methylation measurement across the whole genome. Single-cell DARE is an attractive and scalable approach for concurrent genomic and epigenomic characterization of cells in a heterogeneous population.
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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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Sahajpal, Nikhil, Ashis K. Mondal, Sudha Ananth, Vamsi Kota, Suzanne Hurley, Alka Chaubey, Alex Hastie, Amyn M. Rojiani, Fariborz Rashid-Kolvear, and Ravindra Kolhe. "45. Next-generation cytogenomic characterization of two complex prenatal cases by Saphyr's genome optical mapping." Cancer Genetics 252-253 (April 2021): S16. http://dx.doi.org/10.1016/j.cancergen.2021.01.056.
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Tsai, Yi-Chien, Chun-Hui Chiao, Ian Yi-Feng Chang, Dow-Tien Chen, Tze-Tze Liu, Kate Hua, Chuan-Hsiung Chang, and Ming-Ta Hsu. "Common Altered Epigenomic Domains in Cancer Cells: Characterization and Subtle Variations." Cancers 3, no. 2 (April 18, 2011): 1996–2013. http://dx.doi.org/10.3390/cancers3021996.
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Jefferys, Stuart R., Samuel D. Burgos, Jackson J. Peterson, Sara R. Selitsky, Anne-Marie W. Turner, Lindsey I. James, Yi-Hsuan Tsai, et al. "Epigenomic characterization of latent HIV infection identifies latency regulating transcription factors." PLOS Pathogens 17, no. 2 (February 26, 2021): e1009346. http://dx.doi.org/10.1371/journal.ppat.1009346.
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Transcriptional silencing of HIV in CD4 T cells generates a reservoir of latently infected cells that can reseed infection after interruption of therapy. As such, these cells represent the principal barrier to curing HIV infection, but little is known about their characteristics. To further our understanding of the molecular mechanisms of latency, we characterized a primary cell model of HIV latency in which infected cells adopt heterogeneous transcriptional fates. In this model, we observed that latency is a stable, heritable state that is transmitted through cell division. Using Assay of Transposon-Accessible Chromatin sequencing (ATACseq) we found that latently infected cells exhibit greatly reduced proviral accessibility, indicating the presence of chromatin-based structural barriers to viral gene expression. By quantifying the activity of host cell transcription factors, we observe elevated activity of Forkhead and Kruppel-like factor transcription factors (TFs), and reduced activity of AP-1, RUNX and GATA TFs in latently infected cells. Interestingly, latency reversing agents with different mechanisms of action caused distinct patterns of chromatin reopening across the provirus. We observe that binding sites for the chromatin insulator CTCF are highly enriched in the differentially open chromatin of infected CD4 T cells. Furthermore, depletion of CTCF inhibited HIV latency, identifying this factor as playing a key role in the initiation or enforcement of latency. These data indicate that HIV latency develops preferentially in cells with a distinct pattern of TF activity that promotes a closed proviral structure and inhibits viral gene expression. Furthermore, these findings identify CTCF as a novel regulator of HIV latency.
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Berglund, Anders, Clarisse Muenyi, Erin M. Siegel, Abidemi Ajidahun, Steven A. Eschrich, Denise Wong, Leah E. Hendrick, et al. "Characterization of Epigenomic Alterations in HPV16+ Head and Neck Squamous Cell Carcinomas." Cancer Epidemiology, Biomarkers & Prevention 31, no. 4 (January 21, 2022): 858–69. http://dx.doi.org/10.1158/1055-9965.epi-21-0922.
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Abstract Background: Epigenetic changes associated with human papillomavirus (HPV)–driven tumors have been described; however, HPV type–specific alterations are less well understood. We sought to compare HPV16-specific methylation changes with those in virus-unassociated head and neck squamous cell carcinomas (HNSCC). Methods: Within The Cancer Genome Atlas, 59 HPV16+ HNSCC, 238 nonviral HNSCC (no detectable HPV or other viruses), and 50 normal head and neck tissues were evaluated. Significant differentially methylated regions (DMR) were selected, and key associated genes were identified. Partial least squares models were generated to predict HPV16 status in additional independent samples. Results: HPV infection in HNSCC is associated with type-specific methylomic profiles. Multiple significant DMRs were identified between HPV16+, nonviral, and normal samples. The most significant differentially methylated genes, SYCP2, MSX2, HLTF, PITX2, and GRAMD4, demonstrated HPV16-associated methylation patterns with corresponding alterations in gene expression. Phylogenetically related HPV types (alpha-9 species; HPV31, HPV33, and HPV35) demonstrated a similar methylation profile to that of HPV16 but differed from those seen in other types, such as HPV18 and 45 (alpha-7). Conclusions: HNSCC linked to HPV16 and types from the same alpha species are associated with a distinct methylation profile. This HPV16-associated methylation pattern is also detected in cervical cancer and testicular germ cell tumors. We present insights into both shared and unique methylation alterations associated with HPV16+ tumors and may have implications for understanding the clinical behavior of HPV-associated HNSCC. Impact: HPV type–specific methylomic changes may contribute to understanding biologic mechanisms underlying differences in clinical behavior among different HPV+ and HPV− HNSCC.
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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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Azawi, Shaymaa, Thomas Liehr, Martina Rincic, and Mattia Manferrari. "Molecular Cytogenomic Characterization of the Murine Breast Cancer Cell Lines C-127I, EMT6/P and TA3 Hauschka." International Journal of Molecular Sciences 21, no. 13 (July 1, 2020): 4716. http://dx.doi.org/10.3390/ijms21134716.
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Background: To test and introduce effective and less toxic breast cancer (BC) treatment strategies, animal models, including murine BC cell lines, are considered as perfect platforms. Strikingly, the knowledge on the genetic background of applied BC cell lines is often sparse though urgently necessary for their targeted and really justified application. Methods: In this study, we performed the first molecular cytogenetic characterization for three murine BC cell lines C-127I, EMT6/P and TA3 Hauschka. Besides fluorescence in situ hybridization-banding, array comparative genomic hybridization was also applied. Thus, overall, an in silico translation for the detected imbalances and chromosomal break events in the murine cell lines to the corresponding homologous imbalances in humans could be provided. The latter enabled a comparison of the murine cell line with human BC cytogenomics. Results: All three BC cell lines showed a rearranged karyotype at different stages of complexity, which can be interpreted carefully as reflectance of more or less advanced tumor stages. Conclusions: Accordingly, the C-127I cell line would represent the late stage BC while the cell lines EMT6/P and TA3 Hauschka would be models for the premalignant or early BC stage and an early or benign BC, respectively. With this cytogenomic information provided, these cell lines now can be applied really adequately in future research studies.
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Fiñana, Claudia, Noel Gómez-Molina, Sandra Alonso-Moreno, and Laura Belver. "Genomic and Epigenomic Landscape of Juvenile Myelomonocytic Leukemia." Cancers 14, no. 5 (March 4, 2022): 1335. http://dx.doi.org/10.3390/cancers14051335.
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Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm of early childhood. Most of JMML patients experience an aggressive clinical course of the disease and require hematopoietic stem cell transplantation, which is currently the only curative treatment. JMML is characterized by RAS signaling hyperactivation, which is mainly driven by mutations in one of five genes of the RAS pathway, including PTPN11, KRAS, NRAS, NF1, and CBL. These driving mutations define different disease subtypes with specific clinico-biological features. Secondary mutations affecting other genes inside and outside the RAS pathway contribute to JMML pathogenesis and are associated with a poorer prognosis. In addition to these genetic alterations, JMML commonly presents aberrant epigenetic profiles that strongly correlate with the clinical outcome of the patients. This observation led to the recent publication of an international JMML stratification consensus, which defines three JMML clinical groups based on DNA methylation status. Although the characterization of the genomic and epigenomic landscapes in JMML has significantly contributed to better understand the molecular mechanisms driving the disease, our knowledge on JMML origin, cell identity, and intratumor and interpatient heterogeneity is still scarce. The application of new single-cell sequencing technologies will be critical to address these questions in the future.
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Chai, Hongyan, Fang Xu, Autumn DiAdamo, Brittany Grommisch, Huanzhi Mao, and Peining Li. "Cytogenomic Characterization of Giant Ring or Rod Marker Chromosome in Four Cases of Well-Differentiated and Dedifferentiated Liposarcoma." Case Reports in Genetics 2022 (April 12, 2022): 1–6. http://dx.doi.org/10.1155/2022/6341207.
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Chromosome and array comparative genomic hybridization (aCGH) analyses were performed on two cases of well-differentiated liposarcoma (WDLPS) and two cases of dedifferentiated liposarcoma (DDLPS). The results revealed the characteristic giant ring (GR) or giant rod marker (GRM) chromosomes in all four cases and amplification of numerous somatic copy number alterations (SCNAs) involving a core segment of 12q14.1q15 and other chromosomal regions in three cases. The levels of amplification for oncogenes OS9, CDK4, HMGA2, NUP107, MDM2, YEATS4, and FRS2 at the core segment or other SCNAs should be characterized to facilitate pathologic correlation and prognostic prediction. Further studies for the initial cellular crisis event affecting chromosome intermingling regions for cell-type specific gene regulation may reveal the underlying mutagenesis mechanism for GR and GRM in WDLPS and DDLPS.
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Kumar Mamidi, Tarun Karthik, Jiande Wu, and Chindo Hicks. "Elucidation of the Genomic-Epigenomic Interaction Landscape of Aggressive Prostate Cancer." BioMed Research International 2021 (January 13, 2021): 1–15. http://dx.doi.org/10.1155/2021/6641429.
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Background. Majority of prostate cancer (PCa) deaths are attributed to localized high-grade aggressive tumours which progress rapidly to metastatic disease. A critical unmet need in clinical management of PCa is discovery and characterization of the molecular drivers of aggressive tumours. The development and progression of aggressive PCa involve genetic and epigenetic alterations occurring in the germline, somatic (tumour), and epigenomes. To date, interactions between genes containing germline, somatic, and epigenetic mutations in aggressive PCa have not been characterized. The objective of this investigation was to elucidate the genomic-epigenomic interaction landscape in aggressive PCa to identify potential drivers aggressive PCa and the pathways they control. We hypothesized that aggressive PCa originates from a complex interplay between genomic (both germline and somatic mutations) and epigenomic alterations. We further hypothesized that these complex arrays of interacting genomic and epigenomic factors affect gene expression, molecular networks, and signaling pathways which in turn drive aggressive PCa. Methods. We addressed these hypotheses by performing integrative data analysis combining information on germline mutations from genome-wide association studies with somatic and epigenetic mutations from The Cancer Genome Atlas using gene expression as the intermediate phenotype. Results. The investigation revealed signatures of genes containing germline, somatic, and epigenetic mutations associated with aggressive PCa. Aberrant DNA methylation had effect on gene expression. In addition, the investigation revealed molecular networks and signalling pathways enriched for germline, somatic, and epigenetic mutations including the STAT3, PTEN, PCa, ATM, AR, and P53 signalling pathways implicated in aggressive PCa. Conclusions. The study demonstrated that integrative analysis combining diverse omics data is a powerful approach for the discovery of potential clinically actionable biomarkers, therapeutic targets, and elucidation of oncogenic interactions between genomic and epigenomic alterations in aggressive PCa.
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Mathur, Radhika, Sriranga Iyyanki, Stephanie Hilz, Chibo Hong, Joanna Phillips, Susan Chang, Feng Yue, and Joseph Costello. "EPCO-31. EPIGENOMIC INTRATUMORAL HETEROGENEITY OF GLIOBLASTOMA IN THREE-DIMENSIONAL SPACE." Neuro-Oncology 22, Supplement_2 (November 2020): ii76. http://dx.doi.org/10.1093/neuonc/noaa215.310.
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Abstract Treatment failure in glioblastoma is often attributed to intratumoral heterogeneity (ITH), which fosters tumor evolution and generation of therapy-resistant clones. While ITH in glioblastoma has been well-characterized at the genomic and transcriptomic levels, the extent of ITH at the epigenomic level and its biological and clinical significance are not well understood. In collaboration with neurosurgeons, neuropathologists, and biomedical imaging experts, we have established a novel topographical approach towards characterizing epigenomic ITH in three-dimensional (3-D) space. We utilize pre-operative MRI scans to define tumor volume and then utilize 3-D surgical neuro-navigation to intra-operatively acquire 10+ samples representing maximal anatomical diversity. The precise spatial location of each sample is mapped by 3-D coordinates, enabling tumors to be visualized in 360-degrees and providing unprecedented insight into their spatial organization and patterning. For each sample, we conduct assay for transposase-accessible chromatin using sequencing (ATAC-Seq), which provides information on the genomic locations of open chromatin, DNA-binding proteins, and individual nucleosomes at nucleotide resolution. We additionally conduct whole-exome sequencing and RNA sequencing for each spatially mapped sample. Integrative analysis of these datasets reveals distinct patterns of chromatin accessibility within glioblastoma tumors, as well as their associations with genetically defined clonal expansions. Our analysis further reveals how differences in chromatin accessibility within tumors reflect underlying transcription factor activity at gene regulatory elements, including both promoters and enhancers, and drive expression of particular gene expression sets, including neuronal and immune programs. Collectively, this work provides the most comprehensive characterization of epigenomic ITH to date, establishing its importance for driving tumor evolution and therapy resistance in glioblastoma. As a resource for further investigation, we have provided our datasets on an interactive data sharing platform – The 3D Glioma Atlas – that enables 360-degree visualization of both genomic and epigenomic ITH.
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Feng, Yilong, Shentong Tao, Pengyue Zhang, Francesco Rota Sperti, Guanqing Liu, Xuejiao Cheng, Tao Zhang, et al. "Epigenomic features of DNA G-quadruplexes and their roles in regulating rice gene transcription." Plant Physiology 188, no. 3 (December 6, 2021): 1632–48. http://dx.doi.org/10.1093/plphys/kiab566.
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Abstract A DNA G-quadruplex (G4) is a non-canonical four-stranded nucleic acid structure involved in many biological processes in mammals. The current knowledge on plant DNA G4s, however, is limited; whether and how DNA G4s impact gene expression in plants is still largely unknown. Here, we applied a protocol referred to as BG4-DNA-IP-seq followed by a comprehensive characterization of DNA G4s in rice (Oryza sativa L.); we next integrated dG4s (experimentally detectable G4s) with existing omics data and found that dG4s exhibited differential DNA methylation between transposable element (TE) and non-TE genes. dG4 regions displayed genic-dependent enrichment of epigenomic signatures; finally, we showed that these sites displayed a positive association with expression of DNA G4-containing genes when located at promoters, and a negative association when located in the gene body, suggesting localization-dependent promotional/repressive roles of DNA G4s in regulating gene transcription. This study reveals interrelations between DNA G4s and epigenomic signatures, as well as implicates DNA G4s in modulating gene transcription in rice. Our study provides valuable resources for the functional characterization or bioengineering of some of key DNA G4s in rice.
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Oliveira, Pedro H., John W. Ribis, Elizabeth M. Garrett, Dominika Trzilova, Alex Kim, Ognjen Sekulovic, Edward A. Mead, et al. "Epigenomic characterization of Clostridioides difficile finds a conserved DNA methyltransferase that mediates sporulation and pathogenesis." Nature Microbiology 5, no. 1 (November 25, 2019): 166–80. http://dx.doi.org/10.1038/s41564-019-0613-4.
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Zmuda, Erik. "Comprehensive Characterization of Genomic, Transcriptomic and Epigenomic Artifacts Introduced in Formalin-Fixed, Paraffin-Embedded Tissues." Cancer Genetics 214-215 (August 2017): 41. http://dx.doi.org/10.1016/j.cancergen.2017.04.029.
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Pires, A. S., H. G. Azinheira, A. Cabral, S. Tavares, D. Tavares, M. Castro, V. Várzea, et al. "Cytogenomic characterization ofColletotrichum kahawae, the causal agent of coffee berry disease, reveals diversity in minichromosome profiles and genome size expansion." Plant Pathology 65, no. 6 (December 14, 2015): 968–77. http://dx.doi.org/10.1111/ppa.12479.
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Puiggros, Anna, Mar Mallo, Marta Salido, Ana Gómez-García, Adela Cisneros, Rocío García-Serra, Celia González-Gil, et al. "Pilot Inter-Laboratory Comparison Study of Optical Genome Mapping Analysis for Cytogenomic Characterization of Hematological Malignancies: A Spanish Multicentric Study." Blood 140, Supplement 1 (November 15, 2022): 4981–83. http://dx.doi.org/10.1182/blood-2022-166293.
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Pan, Heng, Yanwen Jiang, David Redmond, Kui Nie, Leandro Cerchietti, Rita Shaknovich, Ari M. Melnick, Wayne Tam, and Olivier Elemento. "Epigenomic Evolution In Diffuse Large B-Cell Lymphomas." Blood 122, no. 21 (November 15, 2013): 634. http://dx.doi.org/10.1182/blood.v122.21.634.634.
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Abstract Diffuse Large B-cell Lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. It is a heterogeneous disease in which one third of patients either do not respond to treatment or relapse within five years after chemotherapy. It is unclear whether epigenetic alterations are responsible for B cell lymphomas relapse phenotypes, such as increased aggressiveness and chemoresistance. To investigate how the B cell lymphoma epigenome evolves upon chemotherapy, we used Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) to profile DNA methylation genome-wide in primary matched diagnosis-relapse DLBCL samples. We interrogated 13 pairs of DLBCL diagnosis tumors and their matched relapse samples. In addition, we performed methylation profiling of normal tonsilar B cell subsets (Naïve and germinal center B cells) from two healthy human individuals. ERRBS provided DNA methylation levels at 3-4M CpG sites. When combining methylation levels from all interrogated CpG sites, we observed increased DNA methylation levels at CpG-islands (CGIs; p=3.5e-9, t-test) in DLBCLs compared to normal B cells, and stable or slightly decreasing methylation levels outside of CGIs (>10 kb away from known CGIs; p=0.057, t-test). There was no significant change in average DNA methylation levels from diagnosis to relapse either at CGIs or outside of CGIs. However, when we investigated DNA methylation changes at gene promoters, we identified 107 consistently differentially methylated promoters between diagnosis and relapse (> 10% DNA methylation alteration and p < 0.05, paired t-test). Pathway analysis of the corresponding genes using iPAGE identified several pathways and processes associated with either hyper or hypo-methylated genes in relapse, demonstrating that methylation changes associated with relapse are functionally coherent. For example, several genes with TGF-beta receptor activity displayed lower DNA methylation in relapse. Taking advantage of single CpG resolution and high coverage provided by ERRBS, we then sought to investigate the extent of allele-specific methylation (ASM) levels in normal tissues and DLBCL patients. We found increased ASM levels in DLBCLs compared to normal tissues (p=0.0011, t-test) confirming observations in solid tumors. There was no significant change in ASM levels from diagnosis to relapse (p=0.24, t-test). These results suggest that methylation changes associated with lymphomagenesis might frequently involve one allele only, perhaps due to differential nuclear localization of individual chromosomes. However allele-specific methylation may not play a key role in lymphoma progression. Finally, we investigated whether intra-tumor methylation heterogeneity at diagnosis would predict whether a DLBCL patient would relapse. We quantified intra-tumor methylation heterogeneity using a statistical approach based on the probability that two randomly sampled DNA molecules from the tumor cell populations differ from each other in their methylation pattern. We found decreased intra-sample methylation heterogeneity in DLBCLs compared to normal germinal center B cells (p=1.9e-4, t-test), consistent with the clonal origin of tumors. 12 out of 13 pairs also displayed decreased methylation heterogeneity from diagnosis to relapse, which is also consistent with clonal selection upon chemotherapy treatment. We then performed ERRBS on primary tumors from 8 DLBCL patients who have not relapsed five years after treatment. We found that non-relapse patients displayed significantly lower intra-tumor methylation heterogeneity as compared to that of the relapsed patients (p=0.047, t-test), which suggests that increased epigenetic diversity within a population of tumor cells at diagnosis might fuel the Darwinian evolutionary process underlying relapse. We also looked at genetic clonal heterogeneity based on next-generation sequencing of somatic hypermutation profiles in IGH VDJ sequences, but found no differences between relapsed and not relapsed patients (p=0.22, Wilcoxon test). This suggests that epigenetic heterogeneity plays a more substantial role than clonal heterogeneity in fueling the relapse phenotype. In summary, this study provides the first comprehensive characterization of aberrations in DNA methylation in relapse DLBCLs and identified epigenetic diversity in DLBCLs as a potential predictor of relapse. Disclosures: No relevant conflicts of interest to declare.
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Mendizábal-Castillero, Marco, Manuel Alejandro Merlo, Ismael Cross, María Esther Rodríguez, and Laureana Rebordinos. "Genomic Characterization of hox Genes in Senegalese Sole (Solea senegalensis, Kaup 1858): Clues to Evolutionary Path in Pleuronectiformes." Animals 12, no. 24 (December 19, 2022): 3586. http://dx.doi.org/10.3390/ani12243586.
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The Senegalese sole (Solea senegalensis, Kaup 1858), a marine flatfish, belongs to the Pleuronectiformes order. It is a commercially important species for fisheries and aquaculture. However, in aquaculture, several production bottlenecks have still to be resolved, including skeletal deformities and high mortality during the larval and juvenile phase. The study aims to characterize the hox gene clusters in S. senegalensis to understand better the developmental and metamorphosis process in this species. Using a BAC library, the clones that contain hox genes were isolated, sequenced by NGS and used as BAC-FISH probes. Subsequently the hox clusters were studied by sequence analysis, comparative genomics, and cytogenetic and phylogenetic analysis. Cytogenetic analysis demonstrated the localization of four BAC clones on chromosome pairs 4, 12, 13, and 16 of the Senegalese sole cytogenomic map. Comparative and phylogenetic analysis showed a highly conserved organization in each cluster and different phylogenetic clustering in each hox cluster. Analysis of structural and repetitive sequences revealed accumulations of polymorphisms mediated by repetitive elements in the hoxba cluster, mainly retroelements. Therefore, a possible loss of the hoxb7a gene can be established in the Pleuronectiformes lineage. This work allows the organization and regulation of hox clusters to be understood, and is a good base for further studies of expression patterns.
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Zhang, Zhuzhu, Jingtian Zhou, Pengcheng Tan, Yan Pang, Angeline C. Rivkin, Megan A. Kirchgessner, Elora Williams, et al. "Epigenomic diversity of cortical projection neurons in the mouse brain." Nature 598, no. 7879 (October 6, 2021): 167–73. http://dx.doi.org/10.1038/s41586-021-03223-w.
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AbstractNeuronal cell types are classically defined by their molecular properties, anatomy and functions. Although recent advances in single-cell genomics have led to high-resolution molecular characterization of cell type diversity in the brain1, neuronal cell types are often studied out of the context of their anatomical properties. To improve our understanding of the relationship between molecular and anatomical features that define cortical neurons, here we combined retrograde labelling with single-nucleus DNA methylation sequencing to link neural epigenomic properties to projections. We examined 11,827 single neocortical neurons from 63 cortico-cortical and cortico-subcortical long-distance projections. Our results showed unique epigenetic signatures of projection neurons that correspond to their laminar and regional location and projection patterns. On the basis of their epigenomes, intra-telencephalic cells that project to different cortical targets could be further distinguished, and some layer 5 neurons that project to extra-telencephalic targets (L5 ET) formed separate clusters that aligned with their axonal projections. Such separation varied between cortical areas, which suggests that there are area-specific differences in L5 ET subtypes, which were further validated by anatomical studies. Notably, a population of cortico-cortical projection neurons clustered with L5 ET rather than intra-telencephalic neurons, which suggests that a population of L5 ET cortical neurons projects to both targets. We verified the existence of these neurons by dual retrograde labelling and anterograde tracing of cortico-cortical projection neurons, which revealed axon terminals in extra-telencephalic targets including the thalamus, superior colliculus and pons. These findings highlight the power of single-cell epigenomic approaches to connect the molecular properties of neurons with their anatomical and projection properties.
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Ma, Ki H., and John Svaren. "Epigenetic Control of Schwann Cells." Neuroscientist 24, no. 6 (January 7, 2018): 627–38. http://dx.doi.org/10.1177/1073858417751112.
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The journey of Schwann cells from their origin in the neural crest to their ensheathment and myelination of peripheral nerves is a remarkable one. Their apparent static function in enabling saltatory conduction of mature nerve is not only vital for long-term health of peripheral nerve but also belies an innate capacity of terminally differentiated Schwann cells to radically alter their differentiation status in the face of nerve injury. The transition from migrating neural crest cells to nerve ensheathment, and then myelination of large diameter axons has been characterized extensively and several of the transcriptional networks have been identified. However, transcription factors must also modify chromatin structure during Schwann cell maturation and this review will focus on chromatin modification machinery that is involved in promoting the transition to, and maintenance of, myelinating Schwann cells. In addition, Schwann cells are known to play important regenerative roles after peripheral nerve injury, and information on epigenomic reprogramming of the Schwann cell genome has emerged. Characterization of epigenomic requirements for myelin maintenance and Schwann cell responses to injury will be vital in understanding how the various Schwann cell functions can be optimized to maintain and repair peripheral nerve function.
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Petitpierre, Marc, Ludwig Stenz, and Ariane Paoloni-Giacobino. "Epigenomic Changes after Acupuncture Treatment in Patients Suffering from Burnout." Complementary Medicine Research 29, no. 2 (December 7, 2021): 109–19. http://dx.doi.org/10.1159/000521347.
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<b><i>Introduction:</i></b> The effects of acupuncture treatment in patients suffering from burnout may imply an epigenetic control mediated by DNA methylation changes. In this observational study, a genome-wide characterization of epigenetic changes in blood DNA, before and after acupuncture treatment, was performed in a cohort of 11 patients suffering from burnout. <b><i>Methods:</i></b> Burnout was assessed using the Maslach Burnout Inventory (MBI) and DNA was extracted from blood samples and analyzed by Illumina EPIC BeadChip. <b><i>Results:</i></b> Before acupuncture, all patients suffered of emotional exhaustion (EE) (MBI-EE score, 44 ± 6), 81% suffered of depersonalization (DP) (MBI-DP score, 16 ± 6), and 72% of low feelings of personal accomplishment (PA) (MBI-PA score, 29 ± 9). After acupuncture, all MBI dimensions improved significantly (EE, 16 ± 11 [<i>p</i> = 1.5 × 10<sup>–4</sup>]; DP, 4 ± 5 [<i>p</i> = 5.3 × 10<sup>–4</sup>]; and PA, 40 ± 6 [<i>p</i> = 4.1 × 10<sup>–3</sup>]). For each patient, both methylomes obtained before and after acupuncture co-clustered in the multidimensional scaling plot, indicating a high level of similarity. Genes corresponding to the 10 most differentially methylated CpGs showed enrichment in the brain dopaminergic signaling, steroid synthesis and in the insulin sensitivity pathways. <b><i>Conclusion:</i></b> Acupuncture treatment was found to be highly effective on all burnout dimensions and the epigenetic targets identified were involved in some major disturbances of this syndrome.
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Wu, Sitao, Robert W. Li, Weizhong Li, and Cong-jun Li. "Transcriptome Characterization by RNA-seq Unravels the Mechanisms of Butyrate-Induced Epigenomic Regulation in Bovine Cells." PLoS ONE 7, no. 5 (May 15, 2012): e36940. http://dx.doi.org/10.1371/journal.pone.0036940.
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Leal, Alessandro, David Sidransky, and Mariana Brait. "Tissue and Cell-Free DNA-Based Epigenomic Approaches for Cancer Detection." Clinical Chemistry 66, no. 1 (December 30, 2019): 105–16. http://dx.doi.org/10.1373/clinchem.2019.303594.
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Abstract BACKGROUND Over 9 million people die of cancer each year worldwide, reflecting the unmet need for effective biomarkers for both cancer diagnosis and prognosis. Cancer diagnosis is complex because the majority of malignant tumors present with long periods of latency and lack of clinical presentation at early stages. During carcinogenesis, premalignant cells experience changes in their epigenetic landscapes, such as differential DNA methylation, histone modifications, nucleosome positioning, and higher orders of chromatin changes that confer growth advantage and contribute to determining the biologic phenotype of human cancers. CONTENT Recent progress in microarray platforms and next-generation sequencing approaches has allowed the characterization of abnormal epigenetic patterns genome wide in a large number of cancer cases. The sizable amount of processed data also comes with challenges regarding data management and assessment for effective biomarker exploration to be further applied in prospective clinical trials. Epigenetics-based single or panel tests of genes are being explored for clinical management to fulfill unmet needs in oncology. The advance of these tests to the clinical routine will depend on rigorous, extensive, and independent validation in well-annotated cohort of patients and commercial development of clinical routine–friendly and adequate procedures. SUMMARY In this review we discuss the analytic validation of tissue and cell-free DNA-based epigenomic approaches for early cancer detection, diagnosis, and treatment monitoring and the clinical utility of candidate epigenetic alterations applied to colorectal, glioblastoma, breast, prostate, bladder, and lung cancer management.
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Ramos, Madalena, Rita Carvalho, Elsa Soares da Silva, Ana Paula Ramos, and Pedro Talhinhas. "Pathological and Epidemiological Characterization of First Outbreak of Daylily Rust in Europe and Evaluation of Puccinia hemerocallidis Resistance in Hemerocallis Cultivars." Plants 9, no. 4 (March 31, 2020): 427. http://dx.doi.org/10.3390/plants9040427.
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Daylily rust—caused by Puccinia hemerocallidis—was confined to Eastern Asia until the disease was reported in Oceania, Africa, the Americas and Portugal in the 21st century. Although information on rust resistance of American cultivars is available, little is known about the resistance of European bred cultivars, threating the ornamental sector if the fungus spreads to other European countries. Aiming to provide tools to address this, we analyzed the Portuguese pathogens and characterized rust resistance in a selection of cultivars, while optimizing disease rating scales. Morphologic, genetic and cytogenomic characterization of four isolates reveals narrow diversity and raises the question whether the pathogen may have originated in North- or Central America. Daily records of multiple symptomatologic parameters enabled a detailed disease progress analysis, discriminating cultivars according to their resistance levels and revealing susceptibility as the most common state. Among the tested cultivars, 12 out of 17 began to show symptoms between 6–8 dai and were classified as susceptible. Cultivars ‘Stella d’Oro’, ‘Bitsy’ and ‘Cherry Tiger’ behaved as moderately resistant although the occurrence of late sporulation on leaves suggests incomplete resistance and challenges common rating scales. The identification of resistance sources in European breeding lines is crucial for the sustainable future of daylilies.
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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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Papuc, Sorina Mihaela, Alina Erbescu, Diana Cisleanu, Diana Ozunu, Cristina Enache, Ion Dumitru, Elena Lupoaia Andrus, et al. "Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies." Genes 12, no. 6 (May 30, 2021): 846. http://dx.doi.org/10.3390/genes12060846.
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Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were investigated with an integrated approach, including classical and molecular cytogenetics, array-based comparative genomic hybridization and targeted next generation sequencing (NGS). Various genetic defects were identified in all the patients using our strategy. Targeted NGS revealed known pathogenic mutations as well as rare or unreported variants with deleterious predictions. The mutational screening of the normal karyotype (NK) group identified clinically relevant variants in 86.2% of the patients; in the abnormal cytogenetics group, the mutation detection rate was 87.5%. Overall, the highest mutation prevalence was observed for the NPM1 gene, followed by DNMT3A, FLT3 and NRAS. An unexpected co-occurrence of KMT2A translocation and DNMT3A-R882 was identified; alterations of these genes, which are involved in epigenetic regulation, are considered to be mutually exclusive. A microarray analysis detected CNVs in 25% of the NK AML patients. In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance.
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Baughn, Linda B., Jaclyn A. Biegel, Sarah T. South, Teresa A. Smolarek, Suzanne Volkert, Andrew J. Carroll, Nyla A. Heerema, et al. "Integration of cytogenomic data for furthering the characterization of pediatric B-cell acute lymphoblastic leukemia: a multi-institution, multi-platform microarray study." Cancer Genetics 208, no. 1-2 (January 2015): 1–18. http://dx.doi.org/10.1016/j.cancergen.2014.11.003.
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Gupta, Pravesh, Dapeng Hao, Krishna Bojja Bojja, Tuan Tran, Minghao Dang, Jianzhuo Li, Atul Maheshwari, Nicholas Navin, Linghua Wang, and Krishna Bhat. "833 The epigenomic landscape of human glioma-associated myeloid cells." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A885. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0833.
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BackgroundGliomas are recalcitrant tumors of the central nervous system. The tumor immune microenvironment (TIME) in gliomas is considered immunosuppressive and making it difficult to treat these tumors with conventional immunotherapy approaches, therefore a better characterization of the immune cell repertoire is needed to fully understand the tumor immune contexture. While single-cell RNA-sequencing (scRNA-seq) approaches have revealed the transcriptional heterogeneity, the gene regulatory landscape at the chromatin level is quintessential for a deeper understanding of lineage and signal-dependent transcription factors (TFs) induced in the brain TIME.MethodsWe performed single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) on ~90,000 tumor-associated and sorted CD45+ leukocytes from fourteen genomically classified patients comprising IDH-mutant primary (IMP; n=4), IDH-mutant recurrent (IMR; n=3), IDH-wild type primary (IWP; n=3), or IDH-wild type recurrent (IWR; n=4) gliomas (hereafter referred as glioma subtypes) and two non-glioma brains (NGBs) as controls. The resulting data were quality checked and processed using Cell Ranger ATAC-seq pipeline and trajectory analyses were performed using Monocle2.ResultsUsing scRNA-seq data from matched specimens and gene tagging approaches, we identified twenty-six clusters of myeloid and seventeen clusters of lymphoid populations across and within gliomas. In this study, we exclusively focused on myeloid subpopulations, which were resolved into microglia and non-microglia myeloid cell subsets. Concordant with our scRNA-seq data, we identified all cell types including monocytes, monocyte-derived cells (MDCs), and dendritic cells by using differential gene accessibility (DGE) analyses. Importantly, although MG from all samples clustered differently, NGB and IM subtypes exhibited concordance in DGE and were separate from IWP and IWR subtypes. Reconstruction of the cell trajectories demonstrated that enhancers for TFs related to mesenchymal transition in GBM such as NF-kB and CEBPB were accessible from normal to tumor-associated microglia. On the other hand, tissue-associated macrophages exhibited enhanced calcium-regulated NFAT TF accessibility. Tumor-associated IWP and IWR myeloid cells also showed a gain of DGE of apoptosis and a reduction of proliferation-related genes.ConclusionsOur studies demonstrate that in addition to the previous dogma of myeloid mediated immune suppression that contributes to tumor immune escape, epigenomic reprogramming in the brain TIME leads to unexpected activation of transcriptional pathways that can trigger transdifferentiation and cell death of myeloid cells further promoting tumor progression. In summary, we provide an unparalleled epigenomic landscape of glioma-associated myeloid cells that may have translational implications.AcknowledgementsThis study in Krishna Bhat’s laboratory was supported by the generous philanthropic contributions to The University of Texas (UT) MD Anderson Cancer Center (MDACC) Moon Shots Program™, Marnie Rose Foundation, NIH grants: R21 CA222992 and R01CA225963. This study was partly supported by the UT MDACC start-up research fund to Linghua Wang and CPRIT Single-Core grant RP180684 to Nicholas Navin.Trial RegistrationNAEthics ApprovalThe brain tumor/tissue samples were collected as per MD Anderson internal review board (IRB)-approved protocol numbers LAB03-0687 and, LAB04-0001. One non-tumor brain tissue sample was collected from a patient undergoing neurosurgery for epilepsy as per Baylor College of Medicine IRB-approved protocol number H-13798. All experiments were compliant with the review board of MD Anderson Cancer Center, USA.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal
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Zheng, Dongyang, and Wenli Zhang. "Characterization of Expression and Epigenetic Features of Core Genes in Common Wheat." Genes 13, no. 7 (June 21, 2022): 1112. http://dx.doi.org/10.3390/genes13071112.
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The availability of multiple wheat genome sequences enables us to identify core genes and characterize their genetic and epigenetic features, thereby advancing our understanding of their biological implications within individual plant species. It is, however, largely understudied in wheat. To this end, we reanalyzed genome sequences from 16 different wheat varieties and identified 62,299 core genes. We found that core and non-core genes have different roles in subgenome differentiation. Meanwhile, according to their expression profiles, these core genes can be classified into genes related to tissue development and stress responses, including 3376 genes highly expressed in both spikelets and at high temperatures. After associating with six histone marks and open chromatin, we found that these core genes can be divided into eight sub-clusters with distinct epigenomic features. Furthermore, we found that ca. 51% of the expressed transcription factors (TFs) were marked with both H3K27me3 and H3K4me3, indicative of the bivalency feature, which can be involved in tissue development through the TF-centered regulatory network. Thus, our study provides a valuable resource for the functional characterization of core genes in stress responses and tissue development in wheat.
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Novo-Filho, Gil M., Marília M. Montenegro, Évelin A. Zanardo, Roberta L. Dutra, Alexandre T. Dias, Flavia B. Piazzon, Taís V. M. M. Costa, et al. "Subtelomeric Copy Number Variations: The Importance of 4p/4q Deletions in Patients with Congenital Anomalies and Developmental Disability." Cytogenetic and Genome Research 149, no. 4 (2016): 241–46. http://dx.doi.org/10.1159/000448905.
Full textAbstract:
The most prevalent structural variations in the human genome are copy number variations (CNVs), which appear predominantly in the subtelomeric regions. Variable sizes of 4p/4q CNVs have been associated with several different psychiatric findings and developmental disability (DD). We analyzed 105 patients with congenital anomalies (CA) and developmental and/or intellectual disabilities (DD/ID) using MLPA subtelomeric specific kits (P036 /P070) and 4 of them using microarrays. We found abnormal subtelomeric CNVs in 15 patients (14.3%), including 8 patients with subtelomeric deletions at 4p/4q (53.3%). Additional genomic changes were observed at 1p36, 2q37.3, 5p15.3, 5q35.3, 8p23.3, 13q11, 14q32.3, 15q11.2, and Xq28/Yq12. This indicates the prevalence of independent deletions at 4p/4q, involving PIGG, TRIML2, and FRG1. Furthermore, we identified 15 genes with changes in copy number that contribute to neurological development and/or function, among them CRMP1, SORCS2, SLC25A4, and HELT. Our results highlight the association of genes with changes in copy number at 4p and 4q subtelomeric regions and the DD phenotype. Cytogenomic characterization of additional cases with distal deletions should help clarifying the role of subtelomeric CNVs in neurological diseases.
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Yurkevich, Olga Yu, Tatiana E. Samatadze, Inessa Yu Selyutina, Svetlana I. Romashkina, Svyatoslav A. Zoshchuk, Alexandra V. Amosova, and Olga V. Muravenko. "Molecular Cytogenetics of Eurasian Species of the Genus Hedysarum L. (Fabaceae)." Plants 10, no. 1 (January 4, 2021): 89. http://dx.doi.org/10.3390/plants10010089.
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The systematic knowledge on the genus Hedysarum L. (Fabaceae: Hedysareae) is still incomplete. The species from the section Hedysarum are valuable forage and medicinal resources. For eight Hedysarum species, we constructed the integrated schematic map of their distribution within Eurasia based on currently available scattered data. For the first time, we performed cytogenomic characterization of twenty accessions covering eight species for evaluating genomic diversity and relationships within the section Hedysarum. Based on the intra- and interspecific variability of chromosomes bearing 45S and 5S rDNA clusters, four main karyotype groups were detected in the studied accessions: (1) H.arcticum, H. austrosibiricum, H. flavescens, H. hedysaroides, and H. theinum (one chromosome pair with 45S rDNA and one pair bearing 5S rDNA); (2) H. alpinum and one accession of H. hedysaroides (one chromosome pair with 45S rDNA and two pairs bearing 5S rDNA); (3) H. caucasicum (one chromosome pair with 45S rDNA and one chromosome pair bearing 5S rDNA and 45S rDNA); (4) H. neglectum (two pairs with 45S rDNA and one pair bearing 5S rDNA). The species-specific chromosomal markers detected in karyotypes of H. alpinum, H. caucasicum, and H. neglectum can be useful in taxonomic studies of this section.
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Johann to Berens, Philippe, and Jean Molinier. "Formation and Recognition of UV-Induced DNA Damage within Genome Complexity." International Journal of Molecular Sciences 21, no. 18 (September 12, 2020): 6689. http://dx.doi.org/10.3390/ijms21186689.
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Ultraviolet (UV) light is a natural genotoxic agent leading to the formation of photolesions endangering the genomic integrity and thereby the survival of living organisms. To prevent the mutagenetic effect of UV, several specific DNA repair mechanisms are mobilized to accurately maintain genome integrity at photodamaged sites within the complexity of genome structures. However, a fundamental gap remains to be filled in the identification and characterization of factors at the nexus of UV-induced DNA damage, DNA repair, and epigenetics. This review brings together the impact of the epigenomic context on the susceptibility of genomic regions to form photodamage and focuses on the mechanisms of photolesions recognition through the different DNA repair pathways.
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Sengupta, Soma, Daniel Pomeranz Krummel, and Scott Pomeroy. "The evolution of medulloblastoma therapy to personalized medicine." F1000Research 6 (April 13, 2017): 490. http://dx.doi.org/10.12688/f1000research.10859.1.
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Recent advances in cancer genomics have revolutionized the characterization and classification of medulloblastomas. According to the current WHO guidelines, medulloblastomas are now classified into the following molecularly defined groups: Wnt signaling pathway (WNT)-activated, sonic hedgehog signaling pathway (SHH)-activated and tumor suppressor protein p53 (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH (i.e. group 3 and group 4). Importantly, genomic, epigenomic, and proteomic advances have created a potential paradigm shift in therapeutic options. The challenge now is to (i) translate these observations into new therapeutic approaches and (ii) employ these observations in clinical practice, utilizing the classification following a molecular analysis for diagnosis and application of new subgroup-specific targeted therapeutics.
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Quintanal-Villalonga, Alvaro, Hirokazu Taniguchi, Yingqian A. Zhan, Jacklynn V. Egger, Umesh Bhanot, Juan Qiu, Elisa de Stanchina, et al. "AKT inhibition as a therapeutic strategy to constrain histological transdifferentiation in EGFR-mutant lung adenocarcinoma." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e21166-e21166. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21166.
Full textAbstract:
e21166 Background: In lung adenocarcinomas (LUADs), lineage plasticity drives neuroendocrine (NE) and squamous cell (LUSC) transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is remarkably lower than those of LUAD or de novo LUSC patients. The paucity of transforming clinical specimens amenable for molecular analyses has hindered the identification of histological transformation drivers, and to date no specific therapies aimed to prevent or delay transdifferentiation-led therapy relapse are available for patients at high risk of transformation. Methods: We performed multi-omic profiling of LUAD-to-LUSC and LUAD-to-NE transdifferentiating clinical samples, including comprehensive and integrative genomic (whole exome sequencing), epigenomic (bisulfite sequencing), transcriptomic (RNAseq) and protein (antibody arrays) characterization. Clinical findings were validated in preclinical models including cell lines as well as LUSC- and NE-transdifferentiation patient-derived xenograft models. Results: Our data supports that histological transdifferentiation from LUAD to LUSC or NE tumors is driven by epigenetic remodeling rather than by mutational events, and indicate that transdifferentiated tumors retain epigenomic features of their previous LUAD state. Integrative epigenomic, transcriptomic and protein analysis revealed divergent biological pathways dysregulated for each histological outcome, such as downregulation of RTK signaling and Notch-related genes in NE-transformed tumors, and upregulation of genes involved in Hedgehog and Notch signaling and MYC targets in LUSC-transdifferentiated tumors. Most interestingly, these analyses identified commonly dysregulated pathways in both NE- and LUSC-transdifferentiating tumors, including remarkable downregulation of a variety of immune-related pathways and upregulation of genes involved in AKT signaling and in the PRC2 epigenetic remodeling complex. Concurrent activation of AKT and MYC overexpression induced a squamous phenotype in EGFR-mutant LUAD preclinical models, further accentuated by EGFR inhibition. Pharmacological targeting of AKT in combination with osimertinib delayed both squamous and NE transformation in different EGFR-mutant patient-derived xenograft transdifferentiation models. Conclusions: These results identify common and divergent dysregulated pathways in NE and LUSC transdifferentiation, and nominate AKT as a therapeutic target to prevent the acquisition of resistance to EGFR-targeted therapies through histological transdifferentiation.