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Lisa B Caruso, Kayla A Martin, Elisabetta Lauretti, Michael Hulse, Micheal Siciliano, Lena N Lupey-Green, Aaron Abraham, Tomasz Skorski, Italo Tempera
The enzyme Poly(ADP-ribose) polymerase 1 (PARP1) plays a very important role in the DNA damage response, but its role in numerous aspects is not fully understood. We recently showed that in the absence of DNA damage, PARP1 regulates the expression of the chromatin-modifying enzyme EZH2. Work from other groups has shown that EZH2 participates in the DNA damage response. These combined data suggest that EZH2 could be a target of PARP1 in both untreated and genotoxic agent-treated conditions. In this work we tested the hypothesis that, in response to DNA damage, PARP1 regulates EZH2 activity...
February 13, 2018: Oncotarget
Qi Li, Bai Li, Chengya Dong, Yajie Wang, Qi Li
20(S)-Ginsenoside Rh2 (20(S)-GRh2) exerts important pharmacological effects with regard to the control of human hepatocellular carcinoma (HCC). EZH2 is a potent histone methyltransferase of H3K27me(3), which has been determined as an oncogene in many malignancies. The CDKN2A-2B gene cluster encodes three important tumor suppressors, P14, P15 and P16. In this study, the anticancer effect and molecular mechanism of 20(S)-GRh2 on HCC was investigated. Treatment of HCC cells with 20(S)-GRh2 inhibited cell proliferation, migration and induced cell cycle arrest at the G0/G1 phase, and inhibited tumor growth in vivo...
November 15, 2017: European Journal of Pharmacology
Luciana Simões Rafagnin Marinho, Vitor Braga Rissi, Andressa Guidugli Lindquist, Marcelo Marcondes Seneda, Vilceu Bordignon
Methylation and acetylation of histone H3 at lysine 27 (H3K27) regulate chromatin structure and gene expression during early embryo development. While H3K27 acetylation (H3K27ac) is associated with active gene expression, H3K27 methylation (H3K27me) is linked to transcriptional repression. The aim of this study was to assess the profile of H3K27 acetylation and methylation (mono-, di- and trimethyl) during oocyte maturation and early development in vitro of porcine embryos. Oocytes/embryos were fixed at different developmental stages from germinal vesicle to day 8 blastocysts and submitted to an immunocytochemistry protocol to identify the presence and quantify the immunofluorescence intensity of H3K27ac, H3K27me1, H3K27me2 and H3K27me3...
July 11, 2017: Zygote: the Biology of Gametes and Early Embryos
Jacob K Kresovich, Zhou Zhang, Fang Fang, Yinan Zheng, Marco Sanchez-Guerra, Brian T Joyce, Jia Zhong, Yana Chervona, Sheng Wang, Dou Chang, John P McCracken, Anaite Díaz, Matteo Bonzini, Michele Carugno, Petros Koutrakis, Choong-Min Kang, Shurui Bian, Tao Gao, Hyang-Min Byun, Joel Schwartz, Andrea A Baccarelli, Lifang Hou
CONTEXT: Histone modifications regulate gene expression; dysregulation has been linked with cardiovascular diseases. Associations between histone modification levels and blood pressure in humans are unclear. OBJECTIVE: We examine the relationship between global histone concentrations and various markers of blood pressure. MATERIALS AND METHODS: Using the Beijing Truck Driver Air Pollution Study, we investigated global peripheral white blood cell histone modifications (H3K9ac, H3K9me3, H3K27me3, and H3K36me3) associations with pre- and post-work measurements of systolic (SBP) and diastolic (DBP) blood pressure, mean arterial pressure (MAP), and pulse pressure (PP) using multivariable mixed-effect models...
September 2017: Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals
Shanshan Ai, Xianhong Yu, Yumei Li, Yong Peng, Chen Li, Yanzhu Yue, Ge Tao, Chuanyun Li, William T Pu, Aibin He
RATIONALE: Polycomb repressive complex 2 is a major epigenetic repressor that deposits methylation on histone H3 on lysine 27 (H3K27me) and controls differentiation and function of many cells, including cardiac myocytes. EZH1 and EZH2 are 2 alternative catalytic subunits with partial functional redundancy. The relative roles of EZH1 and EZH2 in heart development and regeneration are unknown. OBJECTIVE: We compared the roles of EZH1 versus EZH2 in heart development and neonatal heart regeneration...
July 7, 2017: Circulation Research
Beatrice Bodega, Federica Marasca, Valeria Ranzani, Alessandro Cherubini, Francesco Della Valle, Maria Victoria Neguembor, Michel Wassef, Alessio Zippo, Chiara Lanzuolo, Massimiliano Pagani, Valerio Orlando
The evolution of chromatin-based epigenetic cell memory may be driven not only by the necessity for cells to stably maintain transcription programs, but also by the need to recognize signals and allow plastic responses to environmental stimuli. The mechanistic role of the epigenome in adult postmitotic tissues, however, remains largely unknown. In vertebrates, two variants of the Polycomb repressive complex (PRC2-Ezh2 and PRC2-Ezh1) control gene silencing via methylation of histone H3 on Lys27 (H3K27me). Here we describe a reversible mechanism that involves a novel isoform of Ezh1 (Ezh1β)...
May 2017: Nature Structural & Molecular Biology
Faizaan Mohammad, Simon Weissmann, Benjamin Leblanc, Deo P Pandey, Jonas W Højfeldt, Itys Comet, Chunqin Zheng, Jens Vilstrup Johansen, Nicolas Rapin, Bo T Porse, Andrey Tvardovskiy, Ole N Jensen, Nagore G Olaciregui, Cinzia Lavarino, Mariona Suñol, Carmen de Torres, Jaume Mora, Angel M Carcaboso, Kristian Helin
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3...
April 2017: Nature Medicine
Elizabeth T Wiles, Eric U Selker
Polycomb Repressive Complex 2 (PRC2) is a multiprotein complex that catalyzes the methylation of lysine 27 on histone H3 (H3K27me). This histone modification is a feature of facultative heterochromatin in many eukaryotes and maintains transcriptional repression established during early development. Understanding how PRC2 targets regions of the genome to be methylated remains poorly understood. Different cell types can show disparate patterns of H3K27me, and chromatin perturbations, such as loss of marks of constitutive heterochromatin, can cause redistribution of H3K27me, implying that DNA sequence, per se, is not sufficient to define the distribution of this mark...
April 2017: Current Opinion in Genetics & Development
Kai Tang, Zhaobo Lang, Heng Zhang, Jian-Kang Zhu
The Arabidopsis ROS1/DEMETER family of 5-methylcytosine (5mC) DNA glycosylases are the first genetically characterized DNA demethylases in eukaryotes. However, the features of ROS1-targeted genomic loci are not well understood. In this study, we characterized ROS1 target loci in Arabidopsis Col-0 and C24 ecotypes. We found that ROS1 preferentially targets transposable elements (TEs) and intergenic regions. Compared with most TEs, ROS1-targeted TEs are closer to protein coding genes, suggesting that ROS1 may prevent DNA methylation spreading from TEs to nearby genes...
October 31, 2016: Nature Plants
Yong Huang, Yijia Mo, Pengyun Chen, Xiaoling Yuan, Funing Meng, Shengwei Zhu, Zhi Liu
SET (Su(var), E(z), and Trithorax) domain-containing proteins play an important role in plant development and stress responses through modifying lysine methylation status of histone. Gossypium raimondii may be the putative contributor of the D-subgenome of economical crops allotetraploid G. hirsutum and G. barbadense and therefore can potentially provide resistance genes. In this study, we identified 52 SET domain-containing genes from G. raimondii genome. Based on conserved sequences, these genes are grouped into seven classes and are predicted to catalyze the methylation of different substrates: GrKMT1 for H3K9me, GrKMT2 and GrKMT7 for H3K4me, GrKMT3 for H3K36me, GrKMT6 for H3K27me, but GrRBCMT and GrS-ET for nonhistones substrate-specific methylation...
2016: Scientific Reports
J N Nichol, D Dupéré-Richer, T Ezponda, J D Licht, W H Miller
Epigenetics, the modification of chromatin without changing the DNA sequence itself, determines whether a gene is expressed, and how much of a gene is expressed. Methylation of lysine 27 on histone 3 (H3K27me), a modification usually associated with gene repression, has established roles in regulating the expression of genes involved in lineage commitment and differentiation. Not surprisingly, alterations in the homeostasis of this critical mark have emerged as a recurrent theme in the pathogenesis of many cancers...
2016: Advances in Cancer Research
S R Gadhia, D O'Brien, F A Barile
The fetal basis of adult disease (FeBAD) theorizes that embryonic challenges initiate pathologies in adult life through epigenetic modification of gene expression. In addition, inheritance of H3K27 methylation marks, especially in vitro, is still controversial. Metals, such as Cd, are known to affect differentiation, DNA repair and epigenetic status in mES cells. We tested the premise that Cd exerts differential toxicity in mouse embryonic stem (mES) cells by targeting total histone protein (THP) production early in stem cell development, while affecting H3K27-mono-methylation (H3K27me(1)) in latter stages of differentiation...
December 25, 2015: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Kirsty Jamieson, Elizabeth T Wiles, Kevin J McNaught, Simone Sidoli, Neena Leggett, Yanchun Shao, Benjamin A Garcia, Eric U Selker
Methylated lysine 27 on histone H3 (H3K27me) marks repressed "facultative heterochromatin," including developmentally regulated genes in plants and animals. The mechanisms responsible for localization of H3K27me are largely unknown, perhaps in part because of the complexity of epigenetic regulatory networks. We used a relatively simple model organism bearing both facultative and constitutive heterochromatin, Neurospora crassa, to explore possible interactions between elements of heterochromatin. In higher eukaryotes, reductions of H3K9me3 and DNA methylation in constitutive heterochromatin have been variously reported to cause redistribution of H3K27me3...
January 2016: Genome Research
Alejandra Badaracco, Eduardo Gorab
Euchromatin and heterochromatin are usually defined by the degree of DNA compaction, gene content and combinations of histone and non-histone proteins. More recent studies on protein location have been able to specify a variety of chromatin types thus adding chromatin configurations other than the two basic reference states. Chromatin research exploiting non-model organisms has the potential to provide novel information related to epigenetic modifications and their impact on chromosome structure and function...
December 2015: Chromosome Research
Edward Curry, Ian Green, Nadine Chapman-Rothe, Elham Shamsaei, Sarah Kandil, Fanny L Cherblanc, Luke Payne, Emma Bell, Thota Ganesh, Nitipol Srimongkolpithak, Joachim Caron, Fengling Li, Anthony G Uren, James P Snyder, Masoud Vedadi, Matthew J Fuchter, Robert Brown
BACKGROUND: Many cancers show aberrant silencing of gene expression and overexpression of histone methyltransferases. The histone methyltransferases (HKMT) EZH2 and EHMT2 maintain the repressive chromatin histone methylation marks H3K27me and H3K9me, respectively, which are associated with transcriptional silencing. Although selective HKMT inhibitors reduce levels of individual repressive marks, removal of H3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducing the expression of genes with multiple repressive marks...
2015: Clinical Epigenetics
Naoe Kotomura, Nobuhiro Harada, Satoru Ishihara
The human CYP19 gene encodes aromatase, which converts androgens to estrogens. CYP19 mRNA variants are transcribed mainly from three promoters. Quantitative RT-PCR was used to measure the relative amounts of each of the three transcripts and determine the on/off state of the promoters. While some of the promoters were silent, CYP19 mRNA production differed among the other promoters, whose estimated transcription levels were 0.001% to 0.1% of that of the TUBB control gene. To investigate the structural aspects of chromatin that were responsible for this wide range of activity of the CYP19 promoters, we used a fractionation protocol, designated SEVENS, which sequentially separates densely packed nucleosomes from dispersed nucleosomes...
2015: PloS One
Pamela Völkel, Barbara Dupret, Xuefen Le Bourhis, Pierre-Olivier Angrand
EZH2 is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2) which catalyzes methylation of histone H3 at lysine 27 (H3K27me) and mediates gene silencing of target genes via local chromatin reorganization. Numerous evidences show that EZH2 plays a critical role in cancer initiation, progression and metastasis, as well as in cancer stem cell biology. Indeed, EZH2 dysregulation alters gene expression programs in various cancer types. The molecular mechanisms responsible for EZH2 alteration appear to be diverse and depending on the type of cancer...
2015: American Journal of Translational Research
Kazuhiro Murata, Shinya Sato, Mayumi Haruta, Takahiro Goshima, Yoshie Chiba, Satoru Takahashi, Jafar Sharif, Haruhiko Koseki, Makoto Nakanishi, Midori Shimada
Epigenetic modifications such as DNA methylation and histone H3 lysine 27 methylation (H3K27me) are repressive marks that silence gene expression. The M phase phosphoprotein (MPP8) associates with proteins involved in both DNA methylation and histone modifications, and therefore, is a potential candidate to mediate crosstalk between repressive epigenetic pathways. Here, by performing immunohistochemical analyses we demonstrate that MPP8 is expressed in the rodent testis, especially in spermatocytes, suggesting a role in spermatogenesis...
March 13, 2015: Biochemical and Biophysical Research Communications
Phillip A Dumesic, Christina M Homer, James J Moresco, Lindsey R Pack, Erin K Shanle, Scott M Coyle, Brian D Strahl, Danica G Fujimori, John R Yates, Hiten D Madhani
We characterize the Polycomb system that assembles repressive subtelomeric domains of H3K27 methylation (H3K27me) in the yeast Cryptococcus neoformans. Purification of this PRC2-like protein complex reveals orthologs of animal PRC2 components as well as a chromodomain-containing subunit, Ccc1, which recognizes H3K27me. Whereas removal of either the EZH or EED ortholog eliminates H3K27me, disruption of mark recognition by Ccc1 causes H3K27me to redistribute. Strikingly, the resulting pattern of H3K27me coincides with domains of heterochromatin marked by H3K9me...
January 15, 2015: Cell
Yukimasa Shibata, Kiyoji Nishiwaki
Maintenance of cell fates is essential for the development and homeostasis of multicellular organisms and involves the preservation of the expression status of selector genes that control many target genes. Epigenetic marks have pivotal roles in the maintenance of gene expression status, as occurs with methylation on lysine 27 of histone H3 (H3K27me) for Hox gene regulation. In contrast, because the levels of histone acetylation decrease during the mitotic phase, acetylated histone has not been believed to contribute to the maintenance of cell fates...
2014: Worm
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