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Examining How the MAFB Transcription Factor Affects Islet β-Cell Function Postnatally.
Cyphert HA, Walker EM, Hang Y, Dhawan S, Haliyur R, Bonatakis L, Avrahami D, Brissova M, Kaestner KH, Bhushan A, Powers AC, Stein R
(2019) Diabetes 68: 337-348
MeSH Terms: Animals, Cells, Cultured, Chromatin Immunoprecipitation, Chromosomes, Artificial, Bacterial, DNA Methylation, Female, Humans, In Vitro Techniques, Insulin-Secreting Cells, Maf Transcription Factors, Large, MafB Transcription Factor, Mice, Mice, Transgenic, Pregnancy, Tryptophan Hydroxylase
Show Abstract · Added January 8, 2019
The sustained expression of the MAFB transcription factor in human islet β-cells represents a distinct difference in mice. Moreover, mRNA expression of closely related and islet β-cell-enriched MAFA does not peak in humans until after 9 years of age. We show that the MAFA protein also is weakly produced within the juvenile human islet β-cell population and that expression is postnatally restricted in mouse β-cells by de novo DNA methylation. To gain insight into how MAFB affects human β-cells, we developed a mouse model to ectopically express in adult mouse β-cells using transcriptional control sequences. Coexpression of MafB with MafA had no overt impact on mouse β-cells, suggesting that the human adult β-cell MAFA/MAFB heterodimer is functionally equivalent to the mouse MafA homodimer. However, MafB alone was unable to rescue the islet β-cell defects in a mouse mutant lacking MafA in β-cells. Of note, transgenic production of MafB in β-cells elevated tryptophan hydroxylase 1 mRNA production during pregnancy, which drives the serotonin biosynthesis critical for adaptive maternal β-cell responses. Together, these studies provide novel insight into the role of MAFB in human islet β-cells.
© 2018 by the American Diabetes Association.
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15 MeSH Terms
Epigenetic modifiers: activities in renal cell carcinoma.
de Cubas AA, Rathmell WK
(2018) Nat Rev Urol 15: 599-614
MeSH Terms: Carcinoma, Renal Cell, Chromatin, Epigenesis, Genetic, Humans, Kidney Neoplasms, Mutation
Show Abstract · Added October 30, 2019
Renal cell carcinomas (RCCs) are a diverse set of malignancies that have recently been shown to harbour mutations in a number of chromatin modifier genes - including PBRM1, SETD2, BAP1, KDM5C, KDM6A, and MLL2 - through high-throughput sequencing efforts. Current research focuses on understanding the biological activities that chromatin modifiers employ to suppress tumorigenesis and on developing clinical approaches that take advantage of this knowledge. Unsurprisingly, several common themes unify the functions of these epigenetic modifiers, particularly regulation of histone post-translational modifications and nucleosome organization. Furthermore, chromatin modifiers also govern processes crucial for DNA repair and maintenance of genomic integrity as well as the regulation of splicing and other key processes. Many chromatin modifiers have additional non-canonical roles in cytoskeletal regulation, which further contribute to genomic stability, expanding the repertoire of functions that might be essential in tumorigenesis. Our understanding of how mutations in chromatin modifiers contribute to tumorigenesis in RCC is improving but remains an area of intense investigation. Importantly, elucidating the activities of chromatin modifiers offers intriguing opportunities for the development of new therapeutic interventions in RCC.
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VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma.
Zhang J, Wu T, Simon J, Takada M, Saito R, Fan C, Liu XD, Jonasch E, Xie L, Chen X, Yao X, Teh BT, Tan P, Zheng X, Li M, Lawrence C, Fan J, Geng J, Liu X, Hu L, Wang J, Liao C, Hong K, Zurlo G, Parker JS, Auman JT, Perou CM, Rathmell WK, Kim WY, Kirschner MW, Kaelin WG, Baldwin AS, Zhang Q
(2018) Science 361: 290-295
MeSH Terms: Animals, Carcinoma, Renal Cell, Chromatin Immunoprecipitation, Female, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Hydroxylation, Kidney Neoplasms, Mice, Mice, SCID, Molecular Targeted Therapy, Mutation, NF-kappa B, Oncogenes, Substrate Specificity, Transcription Factors, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added October 30, 2019
Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples.
Chen H, Li C, Peng X, Zhou Z, Weinstein JN, Cancer Genome Atlas Research Network, Liang H
(2018) Cell 173: 386-399.e12
MeSH Terms: Aneuploidy, B7-H1 Antigen, Chromatin, Databases, Genetic, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Humans, Immunotherapy, Neoplasms, Sequence Analysis, RNA, Survival Rate
Show Abstract · Added October 30, 2019
The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on "chromatin-state" to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas.
Schaub FX, Dhankani V, Berger AC, Trivedi M, Richardson AB, Shaw R, Zhao W, Zhang X, Ventura A, Liu Y, Ayer DE, Hurlin PJ, Cherniack AD, Eisenman RN, Bernard B, Grandori C, Cancer Genome Atlas Network
(2018) Cell Syst 6: 282-300.e2
MeSH Terms: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Basic Helix-Loop-Helix Transcription Factors, Biomarkers, Tumor, Carcinogenesis, Chromatin, Computational Biology, Genes, myc, Genomics, Humans, Neoplasms, Oncogenes, Proteomics, Proto-Oncogene Proteins c-myc, Repressor Proteins, Signal Transduction, Transcription Factors
Show Abstract · Added October 30, 2019
Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Tuning Hsf1 levels drives distinct fungal morphogenetic programs with depletion impairing Hsp90 function and overexpression expanding the target space.
Veri AO, Miao Z, Shapiro RS, Tebbji F, O'Meara TR, Kim SH, Colazo J, Tan K, Vyas VK, Whiteway M, Robbins N, Wong KH, Cowen LE
(2018) PLoS Genet 14: e1007270
MeSH Terms: Blotting, Western, Candida albicans, Chromatin Immunoprecipitation, Genes, Fungal, HSP90 Heat-Shock Proteins, Heat Shock Transcription Factors, Morphogenesis, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, RNA, Temperature, Virulence
Show Abstract · Added November 7, 2019
The capacity to respond to temperature fluctuations is critical for microorganisms to survive within mammalian hosts, and temperature modulates virulence traits of diverse pathogens. One key temperature-dependent virulence trait of the fungal pathogen Candida albicans is its ability to transition from yeast to filamentous growth, which is induced by environmental cues at host physiological temperature. A key regulator of temperature-dependent morphogenesis is the molecular chaperone Hsp90, which has complex functional relationships with the transcription factor Hsf1. Although Hsf1 controls global transcriptional remodeling in response to heat shock, its impact on morphogenesis remains unknown. Here, we establish an intriguing paradigm whereby overexpression or depletion of C. albicans HSF1 induces morphogenesis in the absence of external cues. HSF1 depletion compromises Hsp90 function, thereby driving filamentation. HSF1 overexpression does not impact Hsp90 function, but rather induces a dose-dependent expansion of Hsf1 direct targets that drives overexpression of positive regulators of filamentation, including Brg1 and Ume6, thereby bypassing the requirement for elevated temperature during morphogenesis. This work provides new insight into Hsf1-mediated environmentally contingent transcriptional control, implicates Hsf1 in regulation of a key virulence trait, and highlights fascinating biology whereby either overexpression or depletion of a single cellular regulator induces a profound developmental transition.
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Genome-wide analysis of PDX1 target genes in human pancreatic progenitors.
Wang X, Sterr M, Burtscher I, Chen S, Hieronimus A, Machicao F, Staiger H, Häring HU, Lederer G, Meitinger T, Cernilogar FM, Schotta G, Irmler M, Beckers J, Hrabě de Angelis M, Ray M, Wright CVE, Bakhti M, Lickert H
(2018) Mol Metab 9: 57-68
MeSH Terms: Cell Differentiation, Cells, Cultured, Chromatin Assembly and Disassembly, Diabetes Mellitus, Type 2, Enhancer Elements, Genetic, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-beta, Homeodomain Proteins, Humans, Induced Pluripotent Stem Cells, Insulin-Secreting Cells, Intercellular Signaling Peptides and Proteins, Membrane Proteins, Myeloid Ecotropic Viral Integration Site 1 Protein, Polymorphism, Single Nucleotide, Protein Binding, Regulatory Factor X Transcription Factors, Trans-Activators, Transcription Factor 7-Like 2 Protein
Show Abstract · Added February 6, 2018
OBJECTIVE - Homozygous loss-of-function mutations in the gene coding for the homeobox transcription factor (TF) PDX1 leads to pancreatic agenesis, whereas heterozygous mutations can cause Maturity-Onset Diabetes of the Young 4 (MODY4). Although the function of Pdx1 is well studied in pre-clinical models during insulin-producing β-cell development and homeostasis, it remains elusive how this TF controls human pancreas development by regulating a downstream transcriptional program. Also, comparative studies of PDX1 binding patterns in pancreatic progenitors and adult β-cells have not been conducted so far. Furthermore, many studies reported the association between single nucleotide polymorphisms (SNPs) and T2DM, and it has been shown that islet enhancers are enriched in T2DM-associated SNPs. Whether regions, harboring T2DM-associated SNPs are PDX1 bound and active at the pancreatic progenitor stage has not been reported so far.
METHODS - In this study, we have generated a novel induced pluripotent stem cell (iPSC) line that efficiently differentiates into human pancreatic progenitors (PPs). Furthermore, PDX1 and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify PDX1 transcriptional targets and active enhancer and promoter regions. To address potential differences in the function of PDX1 during development and adulthood, we compared PDX1 binding profiles from PPs and adult islets. Moreover, combining ChIP-seq and GWAS meta-analysis data we identified T2DM-associated SNPs in PDX1 binding sites and active chromatin regions.
RESULTS - ChIP-seq for PDX1 revealed a total of 8088 PDX1-bound regions that map to 5664 genes in iPSC-derived PPs. The PDX1 target regions include important pancreatic TFs, such as PDX1 itself, RFX6, HNF1B, and MEIS1, which were activated during the differentiation process as revealed by the active chromatin mark H3K27ac and mRNA expression profiling, suggesting that auto-regulatory feedback regulation maintains PDX1 expression and initiates a pancreatic TF program. Remarkably, we identified several PDX1 target genes that have not been reported in the literature in human so far, including RFX3, required for ciliogenesis and endocrine differentiation in mouse, and the ligand of the Notch receptor DLL1, which is important for endocrine induction and tip-trunk patterning. The comparison of PDX1 profiles from PPs and adult human islets identified sets of stage-specific target genes, associated with early pancreas development and adult β-cell function, respectively. Furthermore, we found an enrichment of T2DM-associated SNPs in active chromatin regions from iPSC-derived PPs. Two of these SNPs fall into PDX1 occupied sites that are located in the intronic regions of TCF7L2 and HNF1B. Both of these genes are key transcriptional regulators of endocrine induction and mutations in cis-regulatory regions predispose to diabetes.
CONCLUSIONS - Our data provide stage-specific target genes of PDX1 during in vitro differentiation of stem cells into pancreatic progenitors that could be useful to identify pathways and molecular targets that predispose for diabetes. In addition, we show that T2DM-associated SNPs are enriched in active chromatin regions at the pancreatic progenitor stage, suggesting that the susceptibility to T2DM might originate from imperfect execution of a β-cell developmental program.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
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19 MeSH Terms
Power and sample size calculations for high-throughput sequencing-based experiments.
Li CI, Samuels DC, Zhao YY, Shyr Y, Guo Y
(2018) Brief Bioinform 19: 1247-1255
MeSH Terms: Chromatin Immunoprecipitation, Genome-Wide Association Study, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Microbiota, Mutation, Poisson Distribution, Sequence Analysis, RNA
Show Abstract · Added April 3, 2018
Power/sample size (power) analysis estimates the likelihood of successfully finding the statistical significance in a data set. There has been a growing recognition of the importance of power analysis in the proper design of experiments. Power analysis is complex, yet necessary for the success of large studies. It is important to design a study that produces statistically accurate and reliable results. Power computation methods have been well established for both microarray-based gene expression studies and genotyping microarray-based genome-wide association studies. High-throughput sequencing (HTS) has greatly enhanced our ability to conduct biomedical studies at the highest possible resolution (per nucleotide). However, the complexity of power computations is much greater for sequencing data than for the simpler genotyping array data. Research on methods of power computations for HTS-based studies has been recently conducted but is not yet well known or widely used. In this article, we describe the power computation methods that are currently available for a range of HTS-based studies, including DNA sequencing, RNA-sequencing, microbiome sequencing and chromatin immunoprecipitation sequencing. Most importantly, we review the methods of power analysis for several types of sequencing data and guide the reader to the relevant methods for each data type.
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9 MeSH Terms
Molecular basis for PrimPol recruitment to replication forks by RPA.
Guilliam TA, Brissett NC, Ehlinger A, Keen BA, Kolesar P, Taylor EM, Bailey LJ, Lindsay HD, Chazin WJ, Doherty AJ
(2017) Nat Commun 8: 15222
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, Chickens, Chromatin, Crystallography, X-Ray, DNA Primase, DNA Replication, DNA-Directed DNA Polymerase, HEK293 Cells, Humans, Models, Biological, Multifunctional Enzymes, Protein Binding, Protein Domains, Replication Protein A, Xenopus
Show Abstract · Added March 24, 2018
DNA damage and secondary structures can stall the replication machinery. Cells possess numerous tolerance mechanisms to complete genome duplication in the presence of such impediments. In addition to translesion synthesis (TLS) polymerases, most eukaryotic cells contain a multifunctional replicative enzyme called primase-polymerase (PrimPol) that is capable of directly bypassing DNA damage by TLS, as well as repriming replication downstream of impediments. Here, we report that PrimPol is recruited to reprime through its interaction with RPA. Using biophysical and crystallographic approaches, we identify that PrimPol possesses two RPA-binding motifs and ascertained the key residues required for these interactions. We demonstrate that one of these motifs is critical for PrimPol's recruitment to stalled replication forks in vivo. In addition, biochemical analysis reveals that RPA serves to stimulate the primase activity of PrimPol. Together, these findings provide significant molecular insights into PrimPol's mode of recruitment to stalled forks to facilitate repriming and restart.
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17 MeSH Terms
Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.
Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG, Hinoue T, Hoadley KA, Gibb EA, Roszik J, Covington KR, Wu CC, Shinbrot E, Stransky N, Hegde A, Yang JD, Reznik E, Sadeghi S, Pedamallu CS, Ojesina AI, Hess JM, Auman JT, Rhie SK, Bowlby R, Borad MJ, Cancer Genome Atlas Network, Zhu AX, Stuart JM, Sander C, Akbani R, Cherniack AD, Deshpande V, Mounajjed T, Foo WC, Torbenson MS, Kleiner DE, Laird PW, Wheeler DA, McRee AJ, Bathe OF, Andersen JB, Bardeesy N, Roberts LR, Kwong LN
(2017) Cell Rep 18: 2780-2794
MeSH Terms: Adult, Aged, Aged, 80 and over, Bile Duct Neoplasms, Cholangiocarcinoma, Chromatin, DNA Methylation, Female, Gene Expression Regulation, Neoplastic, Genomics, Humans, Isocitrate Dehydrogenase, Liver, Liver Neoplasms, Male, Middle Aged, Mitochondria, Mutation, Nuclear Proteins, Pancreatic Neoplasms, Promoter Regions, Genetic, RNA, Long Noncoding, RNA, Messenger, Transcription Factors
Show Abstract · Added October 30, 2019
Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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