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Peter J Thompson, Vered Dulberg, Kyung-Mee Moon, Leonard J Foster, Carol Chen, Mohammad M Karimi, Matthew C Lorincz
[This corrects the article DOI: 10.1371/journal.pgen.1004933.].
October 2016: PLoS Genetics
Richard T Timms, Iva A Tchasovnikarova, Robin Antrobus, Gordon Dougan, Paul J Lehner
The histone methyltransferase SETDB1 plays a central role in repressive chromatin processes, but the functional requirement for its binding partner ATF7IP has remained enigmatic. Here, we show that ATF7IP is essential for SETDB1 stability: nuclear SETDB1 protein is degraded by the proteasome upon ablation of ATF7IP. As a result, ATF7IP is critical for repression that requires H3K9 trimethylation by SETDB1, including transgene silencing by the HUSH complex. Furthermore, we show that loss of ATF7IP phenocopies loss of SETDB1 in genome-wide assays...
October 11, 2016: Cell Reports
C Regina, M Compagnone, A Peschiaroli, A M Lena, G Melino, E Candi
No abstract text is available yet for this article.
2016: Cell Death Discovery
Shoichi Takikita, Ryunosuke Muro, Toshiyuki Takai, Takeshi Otsubo, Yuki I Kawamura, Taeko Dohi, Hiroyo Oda, Masayuki Kitajima, Kenshiro Oshima, Masahira Hattori, Takaho A Endo, Tetsuro Toyoda, John Weis, Yoichi Shinkai, Harumi Suzuki
ESET/SETDB1, one of the major histone methyltransferases, catalyzes histone 3 lysine 9 (H3K9) trimethylation. ESET is critical for suppressing expression of retroviral elements in embryonic stem cells; however, its role in the immune system is not known. We found that thymocyte-specific deletion of ESET caused impaired T cell development, with CD8 lineage cells being most severely affected. Increased apoptosis of CD8 single-positive cells was observed, and TCR-induced ERK activation was severely inhibited in ESET(-/-) thymocytes...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Rumi Hachiya, Takuya Shiihashi, Ibuki Shirakawa, Yorihiro Iwasaki, Yoshihiro Matsumura, Yumiko Oishi, Yukiteru Nakayama, Yoshihiro Miyamoto, Ichiro Manabe, Kozue Ochi, Miyako Tanaka, Nobuhito Goda, Juro Sakai, Takayoshi Suganami, Yoshihiro Ogawa
Proinflammatory cytokine production in macrophages involves multiple regulatory mechanisms, which are affected by environmental and intrinsic stress. In particular, accumulating evidence has suggested epigenetic control of macrophage differentiation and function mainly in vitro. SET domain, bifurcated 1 (Setdb1, also known as Eset) is a histone 3 lysine 9 (H3K9)-specific methyltransferase and is essential for early development of embryos. Here we demonstrate that Setdb1 in macrophages potently suppresses Toll-like receptor 4 (TLR4)-mediated expression of proinflammatory cytokines including interleukin-6 through its methyltransferase activity...
2016: Scientific Reports
Carla Cicchini, Cecilia Battistelli, Marco Tripodi
No abstract text is available yet for this article.
June 3, 2016: Chinese Clinical Oncology
Angeline Eymery, Zichuan Liu, Evgeniy A Ozonov, Michael B Stadler, Antoine H F M Peters
Oocytes develop the competence for meiosis and early embryogenesis during their growth. Setdb1 is a histone H3 lysine 9 (H3K9) methyltransferase required for post-implantation development and has been implicated in the transcriptional silencing of genes and endogenous retroviral elements (ERVs). To address its role in oogenesis and pre-implantation development, we conditionally deleted Setdb1 in growing oocytes. Loss of Setdb1 expression greatly impaired meiosis. It delayed meiotic resumption, altered the dynamics of chromatin condensation, and impaired kinetochore-spindle interactions, bipolar spindle organization and chromosome segregation in more mature oocytes...
August 1, 2016: Development
Xiang Xiao, Xiaomin Shi, Yihui Fan, Chenglin Wu, Xiaolong Zhang, Laurie Minze, Wentao Liu, Rafik M Ghobrial, Peixiang Lan, Xian Chang Li
T helper 17 (Th17) cells are prominently featured in multiple autoimmune diseases, but the regulatory mechanisms that control Th17 cell responses are poorly defined. Here we found that stimulation of OX40 triggered a robust chromatin remodeling response and produced a "closed" chromatin structure at interleukin-17 (IL-17) locus to inhibit Th17 cell function. OX40 activated the NF-κB family member RelB, and RelB recruited the histone methyltransferases G9a and SETDB1 to the Il17 locus to deposit "repressive" chromatin marks at H3K9 sites, and consequently repressing IL-17 expression...
June 21, 2016: Immunity
Shuhei Koide, Motohiko Oshima, Keiyo Takubo, Satoshi Yamazaki, Eriko Nitta, Atsunori Saraya, Kazumasa Aoyama, Yuko Kato, Satoru Miyagi, Yaeko Nakajima-Takagi, Tetsuhiro Chiba, Hirotaka Matsui, Fumio Arai, Yutaka Suzuki, Hiroshi Kimura, Hiromitsu Nakauchi, Toshio Suda, Yoichi Shinkai, Atsushi Iwama
Setdb1, also known as Eset, is a methyltransferase that catalyzes trimethylation of H3K9 (H3K9me3) and plays an essential role in the silencing of endogenous retroviral elements (ERVs) in the developing embryo and embryonic stem cells (ESCs). Its role in somatic stem cells, however, remains unclear because of the early death of Setdb1-deficient embryos. We demonstrate here that Setdb1 is the first H3K9 methyltransferase shown to be essential for the maintenance of hematopoietic stem and progenitor cells (HSPCs) in mice...
August 4, 2016: Blood
Lidong Sun, Jia Fang
Ubiquitination typically occurs through the sequential action of three enzymes catalyzing ubiquitin activation (E1), conjugation (E2), and ligation (E3) and regulates diverse eukaryotic cellular processes. Although monoubiquitination commonly confers nondegradative activities, mechanisms underlying its temporal and spatial regulation and functional plasticity still remain largely unknown. Here we demonstrate that SETDB1, a major histone H3K9 methyltransferase is monoubiquitinated at the evolutionarily conserved lysine-867 in its SET-Insertion domain...
June 16, 2016: Molecular Cell
Lise Rivière, Laetitia Gérossier, Olivier Hantz, Christine Neuveut
No abstract text is available yet for this article.
May 2016: Médecine Sciences: M/S
Asaf Marco, Tatiana Kisliouk, Tzlil Tabachnik, Aron Weller, Noam Meiri
A maternal high-fat diet (HFD) alters the offspring's feeding regulation, leading to obesity. This phenomenon is partially mediated by aberrant expression of the hypothalamic anorexigenic neuropeptide proopiomelanocortin (POMC). Nevertheless, although some individual offspring suffer from morbid obesity, others escape the malprogramming. It is suggested that this difference is due to epigenetic programming. In this study, we report that in lean offspring of non-HFD-fed dams, essential promoter regions for Pomc expression were enriched with 5-hydroxymethylcytosine (5hmC) together with a reduction in the level of 5-methylcytosine (5mC)...
August 2016: Diabetes
Andrew Keniry, Linden J Gearing, Natasha Jansz, Joy Liu, Aliaksei Z Holik, Peter F Hickey, Sarah A Kinkel, Darcy L Moore, Kelsey Breslin, Kelan Chen, Ruijie Liu, Catherine Phillips, Miha Pakusch, Christine Biben, Julie M Sheridan, Benjamin T Kile, Catherine Carmichael, Matthew E Ritchie, Douglas J Hilton, Marnie E Blewitt
BACKGROUND: The presence of histone 3 lysine 9 (H3K9) methylation on the mouse inactive X chromosome has been controversial over the last 15 years, and the functional role of H3K9 methylation in X chromosome inactivation in any species has remained largely unexplored. RESULTS: Here we report the first genomic analysis of H3K9 di- and tri-methylation on the inactive X: we find they are enriched at the intergenic, gene poor regions of the inactive X, interspersed between H3K27 tri-methylation domains found in the gene dense regions...
2016: Epigenetics & Chromatin
Valentina Alarcon, Sergio Hernández, Lorena Rubio, Francisca Alvarez, Yvo Flores, Manuel Varas-Godoy, Giancarlo V De Ferrari, Michael Kann, Rodrigo A Villanueva, Alejandra Loyola
With about 350 million people chronically infected around the world hepatitis B is a major health problem. Template for progeny HBV synthesis is the viral genome, organized as a minichromosome (cccDNA) inside the hepatocyte nucleus. How viral cccDNA gene expression is regulated by its chromatin structure; more importantly, how the modulation of this structure impacts on viral gene expression remains elusive. Here, we found that the enzyme SetDB1 contributes to setting up a repressed cccDNA chromatin state. This repressive state is activated by the histone lysine demethylase-1 (LSD1)...
2016: Scientific Reports
Ping Yu, Lexiang Ji, Kevin J Lee, Miao Yu, Chuan He, Suresh Ambati, Elizabeth C McKinney, Crystal Jackson, Clifton A Baile, Robert J Schmitz, Richard B Meagher
The reprogramming of cellular memory in specific cell types, and in visceral adipocytes in particular, appears to be a fundamental aspect of obesity and its related negative health outcomes. We explored the hypothesis that adipose tissue contains epigenetically distinct subpopulations of adipocytes that are differentially potentiated to record cellular memories of their environment. Adipocytes are large, fragile, and technically difficult to efficiently isolate and fractionate. We developed fluorescence nuclear cytometry (FNC) and fluorescence activated nuclear sorting (FANS) of cellular nuclei from visceral adipose tissue (VAT) using the levels of the pan-adipocyte protein, peroxisome proliferator-activated receptor gamma-2 (PPARg2), to distinguish classes of PPARg2-Positive (PPARg2-Pos) adipocyte nuclei from PPARg2-Negative (PPARg2-Neg) leukocyte and endothelial cell nuclei...
2016: PloS One
Thomas Longerich
Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers worldwide. Its development is considered a step-wise process in which genetic and epigenetic alterations lead to the activation of oncogenes and the inactivation of tumor suppressor genes. In contrast to genetic alterations, epigenetic changes that include aberrant methylation, histone modification and RNA interference do not alter the genetic code, but affect the level of mRNA transcripts. In addition, these epigenetic alterations may influence each other...
April 1, 2016: Chinese Clinical Oncology
Ravi Sonkar, Catherine A Powell, Mahua Choudhury
Endocrine disruptors, phthalates, may have contributed to recent global obesity health crisis. Our study investigated the potential of benzyl butyl phthalate (BBP) to regulate the mesenchymal stem cell epigenome to drive adipogenesis. BBP exposure enhanced lipid accumulation and adipogenesis in a dose-dependent manner compared to control (P < 0.001). Adipogenesis markers, PPARγ (P < 0.001), C/EBPα (P < 0.01), and aP2 (P < 0.001) were significantly upregulated by increasing concentrations of BBP when compared to DMSO...
May 6, 2016: Molecular and Cellular Endocrinology
Jafar Sharif, Takaho A Endo, Manabu Nakayama, Mohammad M Karimi, Midori Shimada, Kayoko Katsuyama, Preeti Goyal, Julie Brind'Amour, Ming-An Sun, Zhixiong Sun, Tomoyuki Ishikura, Yoko Mizutani-Koseki, Osamu Ohara, Yoichi Shinkai, Makoto Nakanishi, Hehuang Xie, Matthew C Lorincz, Haruhiko Koseki
Repression of endogenous retroviruses (ERVs) in mammals involves several epigenetic mechanisms. Acute loss of the maintenance methyltransferase Dnmt1 induces widespread DNA demethylation and transcriptional activation of ERVs, including CpG-rich IAP (intracisternal A particle) proviruses. Here, we show that this effect is not due simply to a loss of DNA methylation. Conditional deletions reveal that both Dnmt1 and Np95 are essential for maintenance DNA methylation. However, while IAPs are derepressed in Dnmt1-ablated embryos and embryonic stem cells (ESCs), these ERVs remain silenced when Np95 is deleted alone or in combination with Dnmt1...
July 7, 2016: Cell Stem Cell
Qiong Xu, Jennifer Goldstein, Ping Wang, Inder K Gadi, Heather Labreche, Catherine Rehder, Wei-Ping Wang, Allyn McConkie, Xiu Xu, Yong-Hui Jiang
BACKGROUND: The pathogenicity of copy number variations (CNV) in neurodevelopmental disorders is supported by research literature. However, few studies have evaluated the utility and counseling challenges of CNV analysis in clinic. METHODS: We analyzed the findings of CNV studies from a cohort referred for genetics evaluation of autism spectrum disorders (ASD), developmental disability (DD), and intellectual disability (ID). RESULTS: Twenty-two CNV in 21 out of 115 probands are considered to be pathogenic (18...
September 2016: Pediatric Research
Lucia Daxinger, Harald Oey, Luke Isbel, Nadia C Whitelaw, Neil A Youngson, Alex Spurling, Kelly K D Vonk, Emma Whitelaw
The number of reports of paternal epigenetic influences on the phenotype of offspring in rodents is increasing but the molecular events involved remain unclear. Here, we show that haploinsufficiency for the histone 3 lysine 9 methyltransferase Setdb1 in the sire can influence the coat colour phenotype of wild type offspring. This effect occurs when the allele that directly drives coat colour is inherited from the dam, inferring that the effect involves an "in trans" step. The implication of this finding is that epigenetic state of the sperm can alter the expression of genes inherited on the maternally derived chromosomes...
2016: Scientific Reports
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