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https://www.readbyqxmd.com/read/29339137/oxygen-induced-alterations-in-the-expression-of-chromatin-modifying-enzymes-and-the-transcriptional-regulation-of-imprinted-genes
#1
William M Skiles, Avery Kester, Jane H Pryor, Mark E Westhusin, Michael C Golding, Charles R Long
Embryo culture and assisted reproductive technologies have been associated with a disproportionately high number of epigenetic abnormalities in the resulting offspring. However, the mechanisms by which these techniques influence the epigenome remain poorly defined. In this study, we evaluated the capacity of oxygen concentration to influence the transcriptional control of a selection of key enzymes regulating chromatin structure. In mouse embryonic stem cells, oxygen concentrations modulated the transcriptional regulation of the TET family of enzymes, as well as the de novo methyltransferase Dnmt3a...
January 12, 2018: Gene Expression Patterns: GEP
https://www.readbyqxmd.com/read/29234025/h3k14ac-is-linked-to-methylation-of-h3k9-by-the-triple-tudor-domain-of-setdb1
#2
Renata Z Jurkowska, Su Qin, Goran Kungulovski, Wolfram Tempel, Yanli Liu, Pavel Bashtrykov, Judith Stiefelmaier, Tomasz P Jurkowski, Srikanth Kudithipudi, Sara Weirich, Raluca Tamas, Hong Wu, Ludmila Dombrovski, Peter Loppnau, Richard Reinhardt, Jinrong Min, Albert Jeltsch
SETDB1 is an essential H3K9 methyltransferase involved in silencing of retroviruses and gene regulation. We show here that its triple Tudor domain (3TD) specifically binds to doubly modified histone H3 containing K14 acetylation and K9 methylation. Crystal structures of 3TD in complex with H3K14ac/K9me peptides reveal that peptide binding and K14ac recognition occurs at the interface between Tudor domains (TD) TD2 and TD3. Structural and biochemical data demonstrate a pocket switch mechanism in histone code reading, because K9me1 or K9me2 is preferentially recognized by the aromatic cage of TD3, while K9me3 selectively binds to TD2...
December 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29233829/smad3-mediated-recruitment-of-the-methyltransferase-setdb1-eset-controls-snail1-expression-and-epithelial-mesenchymal-transition
#3
Dan Du, Yoko Katsuno, Dominique Meyer, Erine H Budi, Si-Han Chen, Hartmut Koeppen, Hongjun Wang, Rosemary J Akhurst, Rik Derynck
During epithelial-mesenchymal transition (EMT), reprogramming of gene expression is accompanied by histone modifications. Whether EMT-promoting signaling directs functional changes in histone methylation has not been established. We show here that the histone lysine methyltransferase SETDB1 represses EMT and that, during TGF-β-induced EMT, cells attenuate SETDB1 expression to relieve this inhibition. SETDB1 also controls stem cell generation, cancer cell motility, invasion, metastatic dissemination, as well as sensitivity to certain cancer drugs...
December 12, 2017: EMBO Reports
https://www.readbyqxmd.com/read/29228278/zinc-finger-protein-274-regulates-imprinted-expression-of-transcripts-in-prader-willi-syndrome-neurons
#4
Maéva Langouët, Heather R Glatt-Deeley, Michael S Chung, Clémence M Dupont-Thibert, Elodie Mathieux, Erin C Banda, Christopher E Stoddard, Leann Crandall, Marc Lalande
Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay and hyperphagia/obesity and is caused by the absence of paternal contribution to chromosome 15q11-q13. Using induced pluripotent stem cell (iPSC) models of PWS, we previously discovered an epigenetic complex that is comprised of the zinc-finger protein ZNF274 and the SET domain bifurcated 1 (SETDB1) histone H3 lysine 9 (H3K9) methyltransferase and that silences the maternal alleles at the PWS locus. Here, we have knocked out ZNF274 and rescued the expression of silent maternal alleles in neurons derived from PWS iPSC lines, without affecting DNA methylation at the PWS-Imprinting Center (PWS-IC)...
December 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29158805/histone-methyltransferase-setdb1-promotes-the-progression-of-colorectal-cancer-by-inhibiting-the-expression-of-tp53
#5
Keli Chen, Fengjiao Zhang, Jie Ding, Yonghao Liang, Zetao Zhan, Yizhi Zhan, Long-Hua Chen, Yi Ding
SETDB1 is a novel histone methyltransferase associated with the functional tri-methylation of histone H3K9. Although aberrant high expression of SETDB1 was experimentally obversed in a variety of solid tumors, its underlying mechanisms in human carcinogenesis are not well known. In this study, we investigated the expression of SETDB1 in a large cohort of colorectal cancer (CRC) samples and cell lines for the first time. Our findings showed that SETDB1 was highly expressed in majority CRC tissues and cell lines; moreover, up-regulation of SETDB1 was negatively correlated with the survival rate of CRC patients...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29151149/impact-of-xist-rna-on-chromatin-modifications-and-transcriptional-silencing-maintenance-at-different-stages-of-imprinted-x-chromosome-inactivation-in-vole-microtus-levis
#6
Alexander I Shevchenko, Elena V Grigor'eva, Sergey P Medvedev, Irina S Zakharova, Elena V Dementyeva, Eugeny A Elisaphenko, Anastasia A Malakhova, Sophia V Pavlova, Suren M Zakian
In vole Microtus levis, cells of preimplantation embryo and extraembryonic tissues undergo imprinted X chromosome inactivation (iXCI) which is triggered by a long non-coding nuclear RNA, Xist. At early stages of iXCI, chromatin of vole inactive X chromosome is enriched with the HP1 heterochromatin-specific protein, trimethylated H3K9 and H4K20 attributable to constitutive heterochromatin. In the study, using vole trophoblast stem (TS) cells as a model of iXCI, we further investigated chromatin of the inactive X chromosome of M...
November 18, 2017: Chromosoma
https://www.readbyqxmd.com/read/29109980/the-abundance-of-metabolites-related-to-protein-methylation-correlates-with-the-metastatic-capacity-of-human-melanoma-xenografts
#7
Xiaolei Shi, Alpaslan Tasdogan, Fang Huang, Zeping Hu, Sean J Morrison, Ralph J DeBerardinis
Metabolic reprogramming is a major factor in transformation, and particular metabolic phenotypes correlate with oncogenotype, tumor progression, and metastasis. By profiling metabolites in 17 patient-derived xenograft melanoma models, we identified durable metabolomic signatures that correlate with biological features of the tumors. BRAF mutant tumors had metabolomic and metabolic flux features of enhanced glycolysis compared to BRAF wild-type tumors. Tumors that metastasized efficiently from their primary sites had elevated levels of metabolites related to protein methylation, including trimethyllysine (TML)...
November 2017: Science Advances
https://www.readbyqxmd.com/read/29108991/setdb1-mediated-fosb-regulation-via-erk2-is-associated-with-an-increase-in-cell-invasiveness-during-anticancer-drug-treatment-of-a549-human-lung-cancer-cells
#8
Han-Heom Na, Keun-Cheol Kim
We have determined a functional link to the inverse expression of SETDB1 and FosB following anticancer drug treatment. Doxorubicin treatment caused decreased SETDB1 expression and FosB overexpression both at the mRNA and protein levels. The decreased HMTase activity of SETDB1 coincided with altered occupancy across the promoter region of the FosB gene. SETDB1 overexpression decreased the luciferase reporter activity containing the FosB promoter region, but siSETDB1 increased the luciferase reporter activity, suggesting that SETDB1 directly and negatively regulated FosB expression...
November 3, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29066607/cancer-cells-on-your-histone-marks-get-setdb1-silence-retrotransposons-and-go
#9
Luisa Robbez-Masson, Christopher H C Tie, Helen M Rowe
Cancer cells thrive on genetic and epigenetic changes that confer a selective advantage but also need strategies to avoid immune recognition. In this issue, Cuellar et al. (2017. J. Cell Biol https://doi.org/10.1083/jcb.201612160) find that the histone methyltransferase SETDB1 enables acute myeloid leukemia cells to evade sensing of retrotransposons by innate immune receptors.
November 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28981838/an-efficient-method-for-generation-of-bi-allelic-null-mutant-mouse-embryonic-stem-cells-and-its-application-for-investigating-epigenetic-modifiers
#10
Cynthia L Fisher, Hendrik Marks, Lily Ting-Yin Cho, Robert Andrews, Sam Wormald, Thomas Carroll, Vivek Iyer, Peri Tate, Barry Rosen, Hendrik G Stunnenberg, Amanda G Fisher, William C Skarnes
Mouse embryonic stem (ES) cells are a popular model system to study biological processes, though uncovering recessive phenotypes requires inactivating both alleles. Building upon resources from the International Knockout Mouse Consortium (IKMC), we developed a targeting vector for second allele inactivation in conditional-ready IKMC 'knockout-first' ES cell lines. We applied our technology to several epigenetic regulators, recovering bi-allelic targeted clones with a high efficiency of 60% and used Flp recombinase to restore expression in two null cell lines to demonstrate how our system confirms causality through mutant phenotype reversion...
September 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28946896/application-of-dual-reading-domains-as-novel-reagents-in-chromatin-biology-reveals-a-new-h3k9me3-and-h3k36me2-3-bivalent-chromatin-state
#11
Rebekka Mauser, Goran Kungulovski, Corinna Keup, Richard Reinhardt, Albert Jeltsch
BACKGROUND: Histone post-translational modifications (PTMs) play central roles in chromatin-templated processes. Combinations of two or more histone PTMs form unique interfaces for readout and recruitment of chromatin interacting complexes, but the genome-wide mapping of coexisting histone PTMs remains an experimentally difficult task. RESULTS: We introduce here a novel type of affinity reagents consisting of two fused recombinant histone modification interacting domains (HiMIDs) for direct detection of doubly modified chromatin...
September 25, 2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28913972/significance-of-histone-methyltransferase-setdb1-expression-in-colon-adenocarcinoma
#12
Yi-Jung Ho, Yueh-Min Lin, Yen-Chi Huang, Jungshan Chang, Kun-Tu Yeh, Liang-In Lin, Zhiyuan Gong, Tsai-Yu Tzeng, Jeng-Wei Lu
This study investigated the clinical implications of SETDB1 (also known as KMT1E) in human colon adenocarcinoma. Expression levels of SETDB1 proteins were analyzed by immunohistochemistry staining, and tissue microarrays were used to examine expression profiles in human patients. Our results revealed that SETDB1 protein expression was significantly higher in tumor tissue than in normal tissue for the breast, colon, liver, and lung (p < 0.05). Moreover, an analysis with SurvExpress software suggested that elevated expression of SETDB1 mRNA was significantly associated with the overall survival of colon adenocarcinoma patients (p < 0...
November 2017: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
https://www.readbyqxmd.com/read/28891439/the-regulation-of-differentiation-of-mesenchymal-stem-cells-into-skeletal-muscle-a-look-at-signalling-molecules-involved-in-myogenesis
#13
Bethany Hodgson, Reza Mafi, Pouya Mafi, Wasim Khan
Mesenchymal Stem Cells (MSCs) are an attractive option for the development of treatment for musculoskeletal pathologies due to their wide availability, clinical safety and multiple techniques available. Understanding the control of MSC differentiation into skeletal muscle is vital for developing protocols and therapeutic applications that are safe and effective. This paper therefore aims to review the current understanding of factors that regulate the differentiation of MSCs into skeletal muscle. Medline, Embase, Pubmed and Web of Science were searched December 2015 using the terms 'differentia*, skeletal*, skeleton*, myocyt*, myogen* and mesenchym* stem-cell*...
September 6, 2017: Current Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28890329/histone-methyltransferase-setdb1-maintains-survival-of-mouse-spermatogonial-stem-progenitor-cells-via-pten-akt-foxo1-pathway
#14
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 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28887438/-silencing-of-retrotransposons-by-setdb1-inhibits-the-interferon-response-in-acute-myeloid-leukemia
#15
Trinna L Cuellar, Anna-Maria Herzner, Xiaotian Zhang, Yogesh Goyal, Colin Watanabe, Brad A Friedman, Vasantharajan Janakiraman, Steffen Durinck, Jeremy Stinson, David Arnott, Tommy K Cheung, Subhra Chaudhuri, Zora Modrusan, Jonas Martin Doerr, Marie Classon, Benjamin Haley
A propensity for rewiring genetic and epigenetic regulatory networks, thus enabling sustained cell proliferation, suppression of apoptosis, and the ability to evade the immune system, is vital to cancer cell propagation. An increased understanding of how this is achieved is critical for identifying or improving therapeutic interventions. In this study, using acute myeloid leukemia (AML) human cell lines and a custom CRISPR/Cas9 screening platform, we identify the H3K9 methyltransferase SETDB1 as a novel, negative regulator of innate immunity...
November 6, 2017: Journal of Cell Biology
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
#16
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...
October 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28671686/the-methyltransferase-setdb1-regulates-a-large-neuron-specific-topological-chromatin-domain
#17
Yan Jiang, Yong-Hwee Eddie Loh, Prashanth Rajarajan, Teruyoshi Hirayama, Will Liao, Bibi S Kassim, Behnam Javidfar, Brigham J Hartley, Lisa Kleofas, Royce B Park, Benoit Labonte, Seok-Man Ho, Sandhya Chandrasekaran, Catherine Do, Brianna R Ramirez, Cyril J Peter, Julia T C W, Brian M Safaie, Hirofumi Morishita, Panos Roussos, Eric J Nestler, Anne Schaefer, Benjamin Tycko, Kristen J Brennand, Takeshi Yagi, Li Shen, Schahram Akbarian
We report locus-specific disintegration of megabase-scale chromosomal conformations in brain after neuronal ablation of Setdb1 (also known as Kmt1e; encodes a histone H3 lysine 9 methyltransferase), including a large topologically associated 1.2-Mb domain conserved in humans and mice that encompasses >70 genes at the clustered protocadherin locus (hereafter referred to as cPcdh). The cPcdh topologically associated domain (TAD(cPcdh)) in neurons from mutant mice showed abnormal accumulation of the transcriptional regulator and three-dimensional (3D) genome organizer CTCF at cryptic binding sites, in conjunction with DNA cytosine hypomethylation, histone hyperacetylation and upregulated expression...
August 2017: Nature Genetics
https://www.readbyqxmd.com/read/28593442/remodeling-of-heterochromatin-structure-slows-neuropathological-progression-and-prolongs-survival-in-an-animal-model-of-huntington-s-disease
#18
Junghee Lee, Yu Jin Hwang, Yunha Kim, Min Young Lee, Seung Jae Hyeon, Soojin Lee, Dong Hyun Kim, Sung Jae Jang, Hyoenjoo Im, Sun-Joon Min, Hyunah Choo, Ae Nim Pae, Dong Jin Kim, Kyung Sang Cho, Neil W Kowall, Hoon Ryu
Huntington's disease (HD) is an autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. Altered histone modifications and epigenetic mechanisms are closely associated with HD suggesting that transcriptional repression may play a pathogenic role. Epigenetic compounds have significant therapeutic effects in cellular and animal models of HD, but they have not been successful in clinical trials. Herein, we report that dSETDB1/ESET, a histone methyltransferase (HMT), is a mediator of mutant HTT-induced degeneration in a fly HD model...
June 7, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28587163/a-tox21-approach-to-altered-epigenetic-landscapes-assessing-epigenetic-toxicity-pathways-leading-to-altered-gene-expression-and-oncogenic-transformation-in-vitro
#19
REVIEW
Craig L Parfett, Daniel Desaulniers
An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs...
June 1, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28420800/setdb1-plays-an-essential-role-in-maintenance-of-gonocyte-survival-in-pigs
#20
Tiantian Liu, Pengfei Zhang, Tianjiao Li, Xiaoxu Chen, Zhenshuo Zhu, Yinghua Lyu, Xueliang Li, Xiue Tian, Wenxian Zeng
Histone methyltransferase SETDB1 suppresses gene expression and modulates heterochromatin formation through H3K9me2/3. Previous studies have revealed that SETDB1 catalyzes lysine 9 of histone H3 tri-methylation and plays essential roles in maintaining the survival of embryonic stem cells and spermatogonial stem cells in mice. However, the function of SETDB1 in porcine male germ cells remains unclear. The aim of the present study was to reveal the expression profile and function of SETDB1 in porcine germ cells...
July 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
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