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H3K9me3

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https://www.readbyqxmd.com/read/28916764/rapid-and-reversible-epigenome-editing-by-endogenous-chromatin-regulators
#1
Simon M G Braun, Jacob G Kirkland, Emma J Chory, Dylan Husmann, Joseph P Calarco, Gerald R Crabtree
Understanding the causal link between epigenetic marks and gene regulation remains a central question in chromatin biology. To edit the epigenome we developed the FIRE-Cas9 system for rapid and reversible recruitment of endogenous chromatin regulators to specific genomic loci. We enhanced the dCas9-MS2 anchor for genome targeting with Fkbp/Frb dimerizing fusion proteins to allow chemical-induced proximity of a desired chromatin regulator. We find that mSWI/SNF (BAF) complex recruitment is sufficient to oppose Polycomb within minutes, leading to activation of bivalent gene transcription in mouse embryonic stem cells...
September 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28916515/reversing-thyroid-hormone-mediated-repression-of-a-hsv-1-promoter-via-computationally-guided-mutagenesis
#2
Robert W Figliozzi, Feng Chen, Shaochung V Hsia
Thyroid hormones (TH or T3) and their DNA binding nuclear receptors (TRs), direct transcriptional regulation in diverse ways depending on the host cell environment and specific promoter characteristics of TH sensitive genes. This study sought to elucidate the impact on transcriptional repression of nucleotide sequence/orientation within TR binding sites, TR elements, (TREs) of TH sensitive promoters, to better understand ligand dependent transcriptional repression of wild-type promoters. Computational analysis of the HSV-1 thymidine kinase (TK) gene TRE bound by TR and RXR revealed a single TRE point mutation sufficient to reverse the TRE orientation...
September 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28894274/kdm4a-regulates-hif-1-levels-through-h3k9me3
#3
Grzegorz Dobrynin, Tom E McAllister, Katarzyna B Leszczynska, Shaliny Ramachandran, Adam J Krieg, Akane Kawamura, Ester M Hammond
Regions of hypoxia (low oxygen) occur in most solid tumours and cells in these areas are the most aggressive and therapy resistant. In response to decreased oxygen, extensive changes in gene expression mediated by Hypoxia-Inducible Factors (HIFs) contribute significantly to the aggressive hypoxic tumour phenotype. In addition to HIFs, multiple histone demethylases are altered in their expression and activity, providing a secondary mechanism to extend the hypoxic signalling response. In this study, we demonstrate that the levels of HIF-1α are directly controlled by the repressive chromatin mark, H3K9me3...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28890329/histone-methyltransferase-setdb1-maintains-survival-of-mouse-spermatogonial-stem-progenitor-cells-via-pten-akt-foxo1-pathway
#4
Tiantian Liu, Xiaoxu Chen, Tianjiao Li, Xueliang Li, Yinghua Lyu, Xiaoteng Fan, Pengfei Zhang, Wenxian Zeng
Spermatogonial stem cells (SSCs) possess the capacity of self-renewal and differentiation, which are the basis of spermatogenesis. In maintenance of SSC homeostasis, intrinsic/extrinsic factors and various signaling pathways tightly control the fate of SSCs. Methyltransferase SETDB1 (Set domain, bifurcated 1) catalyzes histone H3 lysine 9 (H3K9) trimethylation and represses gene expression. SETDB1 is required for maintaining the survival of spermatogonial stem cells in mice. However, the underlying molecular mechanism remains unclear...
September 7, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28881774/chromatin-remodeling-modulates-radiosensitivity-of-the-daughter-cells-derived-from-cell-population-exposed-to-low-and-high-let-irradiation
#5
Ping Wang, Dexiao Yuan, Fei Guo, Xiaoyan Chen, Lin Zhu, Hang Zhang, Chen Wang, Chunlin Shao
Radiation effects are dependent of linear energy transfer (LET), but it is still obscure whether the daughter cells (DCs) derived from irradiated population are radioresistance and much less the underlying mechanism. With the measurements of survival, proliferation and γH2AX foci, this study shows that the DCs from γ-ray irradiated cells (DCs-γ) became more radioresistant than its parent control without irradiation, but the radiosensitivity of DCs from α-particle irradiated cells (DCs-α) was not altered...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28879500/in-silico-probing-and-biological-evaluation-of-setdb1-eset-targeted-novel-compounds-that-reduce-tri-methylated-histone-h3k9-h3k9me3-level
#6
Insun Park, Yu Jin Hwang, TaeHun Kim, Ambily Nath Indu Viswanath, Ashwini M Londhe, Seo Yun Jung, Kyoung Mi Sim, Sun-Joon Min, Ji Eun Lee, Jihye Seong, Yun Kyung Kim, Kyoung Tai No, Hoon Ryu, Ae Nim Pae
ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a histone lysine methyltransferase (HKMT) and it preferentially tri-methylates lysine 9 of histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington's disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide-competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico-in vitro approach...
September 6, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28855512/atrx-is-a-regulator-of-therapy-induced-senescence-in-human-cells
#7
Marta Kovatcheva, Will Liao, Mary E Klein, Nicolas Robine, Heather Geiger, Aimee M Crago, Mark A Dickson, William D Tap, Samuel Singer, Andrew Koff
Senescence is a state of stable cell cycle exit with important implications for development and disease. Here, we demonstrate that the chromatin remodeling enzyme ATRX is required for therapy-induced senescence. ATRX accumulates in nuclear foci and is required for therapy-induced senescence in multiple types of transformed cells exposed to either DNA damaging agents or CDK4 inhibitors. Mobilization into foci depends on the ability of ATRX to interact with H3K9me3 histone and HP1. Foci form soon after cells exit the cell cycle, before other hallmarks of senescence appear...
August 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28852907/functional-role-of-suv39h1-in-human-renal-tubular-epithelial-cells-under-high-glucose-ambiance
#8
Jiayi Wang, Wenzhe Yan, Xiaofei Peng, Yafeng Jiang, Liyu He, Youming Peng, Xian Chen, Muyao Ye, Hui Zhuo
SUV39H1, the histone methyltransferase (HMTase) of histone H3 lysine 9 trimethylation (H3K9me3), is a known transcriptional repressor of inflammatory genes. The effect of SUV39H1 on inflammatory gene promoters under high-glucose stimulation in vascular smooth muscle cells (VSMCs), macrophages, and cardiomyocytes has been studied, but how SUV39H1 functions in renal tubules under diabetic conditions is unclear. Renal biopsy specimens of ten diabetic nephropathy (DN) subjects and seven non-DN minimal change diseases (MCD) subjects were collected...
August 29, 2017: Inflammation
https://www.readbyqxmd.com/read/28835804/design-of-kdm4-inhibitors-with-antiproliferative-effects-in-cancer-models
#9
Young K Chen, Tiziana Bonaldi, Alessandro Cuomo, Joselyn R Del Rosario, David J Hosfield, Toufike Kanouni, Shih-Chu Kao, Chon Lai, Neethan A Lobo, Jennifer Matuszkiewicz, Andrew McGeehan, Shawn M O'Connell, Lihong Shi, Jeffrey A Stafford, Ryan K Stansfield, James M Veal, Michael S Weiss, Natalie Y Yuen, Michael B Wallace
Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models...
August 10, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28820331/polo-like-kinase-1-plk1-dependent-phosphorylation-of-methylenetetrahydrofolate-reductase-mthfr-regulates-replication-via-histone-methylation
#10
Xueyan Li, Shanshan Nai, Yuehe Ding, Qizhi Geng, Bingtao Zhu, Kai Yu, Wei-Guo Zhu, Meng-Qiu Dong, Xiao-Dong Su, Xingzhi Xu, Jing Li
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the folate cycle and its genetic variations have been associated with various human diseases. Previously we identified that MTHFR is phosphorylated by cyclin-dependent kinase 1 (CDK1) at T34 and MTHFR underlies heterochromatin maintenance marked by H3K9me3 levels. Herein we demonstrate that pT34 creates a binding motif that docks MTHFR to the polo-binding domain (PBD) of polo-like kinase 1 (PLK1), a fundamental kinase that orchestrates many cell cycle events...
August 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28808080/characterization-of-the-human-thyroid-epigenome
#11
Celia Siu, Sam Michael Wiseman, Sitanshu Gakkhar, Alireza Heravi-Moussavi, Misha Bilenky, Annaick Carles, Thomas Sierocinski, Angela Tam, Eric Yang Zhao, Katayoon Kasaian, Richard A Moore, Andrew J Mungall, Blair Walker, Thomas Thomson, Marco A Marra, Martin Hirst, Steven Jones
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...
August 14, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28808048/epigenetic-repression-of-line-1-elements-protects-drug-resistant-cells
#12
(no author information available yet)
H3K9me3-dependent heterochromatin formation maintains drug-tolerant persister (DTP) cell viability.
August 14, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28806616/parvovirus-b19-integration-into-human-cd36-erythroid-progenitor-cells
#13
Tyler Janovitz, Susan Wong, Neal S Young, Thiago Oliveira, Erik Falck-Pedersen
The pathogenic autonomous human parvovirus B19 (B19V) productively infects erythroid progenitor cells (EPCs). Functional similarities between B19V nonstructural protein (NS1), a DNA binding endonuclease, and the Rep proteins of Adeno-Associated Virus (AAV) led us to hypothesize that NS1 may facilitate targeted nicking of the human genome and B19 vDNA integration. We adapted an integration capture sequencing protocol (IC-Seq) to screen B19V infected human CD36+ EPCs for viral integrants, and discovered 40,000 unique B19V integration events distributed throughout the human genome...
August 11, 2017: Virology
https://www.readbyqxmd.com/read/28801683/regulation-of-tumour-related-genes-by-dynamic-epigenetic-alteration-at-enhancer-regions-in-gastric-epithelial-cells-infected-by-epstein-barr-virus
#14
Atsushi Okabe, Sayaka Funata, Keisuke Matsusaka, Hiroe Namba, Masaki Fukuyo, Bahityar Rahmutulla, Motohiko Oshima, Atsushi Iwama, Masashi Fukayama, Atsushi Kaneda
Epstein-Barr virus (EBV) infection is associated with tumours such as Burkitt lymphoma, nasopharyngeal carcinoma, and gastric cancer. We previously showed that EBV(+) gastric cancer presents an extremely high-methylation epigenotype and this aberrant DNA methylation causes silencing of multiple tumour suppressor genes. However, the mechanisms that drive EBV infection-mediated tumorigenesis, including other epigenomic alteration, remain unclear. We analysed epigenetic alterations induced by EBV infection especially at enhancer regions, to elucidate their contribution to tumorigenesis...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28798030/ethanol-exposure-regulates-gabra1-expression-via-histone-deacetylation-at-the-promoter-in-cultured-cortical-neurons
#15
John Peyton Bohnsack, Vraj K Patel, A Leslie Morrow
GABAA-Rs mediate the majority of inhibitory neurotransmission in the adult brain. α1-containing GABAA-Rs are the most prominent subtype in the adult brain, and are important in both homeostatic function and several disease pathologies including alcohol dependence, epilepsy, and stress. Ethanol exposure causes a decrease of α1 transcription and peptide expression both in vivo and in vitro, but the mechanism that controls the transcriptional regulation is unknown. Since ethanol is known to activate epigenetic regulation of gene expression, we tested the hypothesis that ethanol regulates α1 expression through histone modifications in cerebral cortical cultured neurons...
August 10, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28794155/microrna-125b-is-a-key-epigenetic-regulatory-factor-that-promotes-nuclear-transfer-reprogramming
#16
Jingcheng Zhang, Pengxiang Qu, Chuan Zhou, Xin Liu, Xiaonan Ma, Mengyun Wang, Yongsheng Wang, Jianmin Su, Jun Liu, Yong Zhang
Somatic cell nuclear transfer (SCNT)-mediated reprogramming is a rapid, efficient, and sophisticated process that reprograms differentiated somatic cells to a pluripotent state. However, many factors in this elaborate reprogramming process remain largely unknown. Here, we report that the microRNA (miR) miR-125b is an important component of SCNT-mediated reprogramming. Luciferase reporter assay, quantitative PCR and Western blotting demonstrated that miR-125b directly binds the 3'-untranslated region of SUV39H1, encoding the histone-lysine N-methyltransferase SUV39H1, to downregulate histone H3 lysine-9 tri-methylation (H3K9me3) in SCNT embryos...
August 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28790329/kdm4b-mediated-reduction-of-h3k9me3-and-h3k36me3-levels-improves-somatic-cell-reprogramming-into-pluripotency
#17
Jingwei Wei, Jisha Antony, Fanli Meng, Paul MacLean, Rebekah Rhind, Götz Laible, Björn Oback
Correct reprogramming of epigenetic marks is essential for somatic cells to regain pluripotency. Repressive histone (H) lysine (K) methylation marks are known to be stable and difficult to reprogram. In this study, we generated transgenic mice and mouse embryonic fibroblasts (MEFs) for the inducible expression of KDM4B, a demethylase that removes H3 K9 and H3K36 trimethylation (me3) marks (H3K9/36me3). Upon inducing Kdm4b, H3K9/36me3 levels significantly decreased compared to non-induced controls. Concurrently, H3K9me1 levels significantly increased, while H3K9me2 and H3K27me3 remained unchanged...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28781121/repression-of-stress-induced-line-1-expression-protects-cancer-cell-subpopulations-from-lethal-drug-exposure
#18
Gulfem Dilek Guler, Charles Albert Tindell, Robert Pitti, Catherine Wilson, Katrina Nichols, Tommy KaiWai Cheung, Hyo-Jin Kim, Matthew Wongchenko, Yibing Yan, Benjamin Haley, Trinna Cuellar, Joshua Webster, Navneet Alag, Ganapati Hegde, Erica Jackson, Tracy Leah Nance, Paul Garrett Giresi, Kuan-Bei Chen, Jinfeng Liu, Suchit Jhunjhunwala, Jeff Settleman, Jean-Philippe Stephan, David Arnott, Marie Classon
Maintenance of phenotypic heterogeneity within cell populations is an evolutionarily conserved mechanism that underlies population survival upon stressful exposures. We show that the genomes of a cancer cell subpopulation that survives treatment with otherwise lethal drugs, the drug-tolerant persisters (DTPs), exhibit a repressed chromatin state characterized by increased methylation of histone H3 lysines 9 and 27 (H3K9 and H3K27). We also show that survival of DTPs is, in part, maintained by regulators of H3K9me3-mediated heterochromatin formation and that the observed increase in H3K9me3 in DTPs is most prominent over long interspersed repeat element 1 (LINE-1)...
August 14, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28765327/the-kmt1a-gata3-stat3-circuit-is-a-novel-self-renewal-signaling-of-human-bladder-cancer-stem-cells
#19
Tingyi Wen, Zhao Yang, Luyun He, Kaisu Lin, Yun Zhang, Aihua Deng, Yong Liang, Chong Li
Bladder cancer (BC) is one of the most common urinary malignancies worldwide characterized by a high rate of recurrence and no targeted therapy method. Bladder cancer stem cells (BCSCs) play a crucial role in tumor initiation, metastasis and drug-resistance. However, the regulatory signaling and self-renewal mechanisms of BCSCs remain largely unknown. Here, we identified a novel signal, the KMT1A-GATA3-STAT3 circuit, which promoted the self-renewal and tumorigenicity of human BCSCs.<br />Experimental Design: In a discovery step, human BCSCs and bladder cancer non-stem cells (BCNSCs) isolated from primary BC samples #1 and #2, and the BC cell line EJ were analyzed by transcriptome microarray...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28765096/effects-of-bpa-on-global-dna-methylation-and-global-histone-3-lysine-modifications-in-sh-sy5y-cells-an-epigenetic-mechanism-linking-the-regulation-of-chromatin-modifiying-genes
#20
Mine Senyildiz, Ecem Fatma Karaman, Serap Sancar Bas, Pelin Arda Pirincci, Sibel Ozden
Bisphenol A (BPA), an estrogenic endocrine disruptor, is widely used in the production of polycarbonate plastic and epoxy resins, resulting in high risk on human health. In present study we aimed to investigate the effects of BPA on global and gene specific DNA methylation, global histone modifications and regulation of chromatin modifiying enzymes in human neuroblastoma cells (SH-SY5Y). Cells were treated with BPA at 0.1, 1 and 10μM concentrations for 48 and 96h. IC50 value of BPA was determined as 183 and 129μM in SH-SY5Y cells after 24h by MTT and NRU tests, respectively...
October 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
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