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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...
December 8, 2016: 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
Laura J Gaydos, Wenchao Wang, Susan Strome
For proper development, cells must retain patterns of gene expression and repression through cell division. Repression via methylation of histone H3 on Lys27 (H3K27me) by Polycomb repressive complex 2 (PRC2) is conserved, but its transmission is not well understood. Our studies suggest that PRC2 represses the X chromosomes in Caenorhabditis elegans germ cells, and this repression is transmitted to embryos by both sperm and oocytes. By generating embryos containing some chromosomes with and some without H3K27me, we show that, without PRC2, H3K27me is transmitted to daughter chromatids through several rounds of cell division...
September 19, 2014: Science
Teresa Ezponda, Jonathan D Licht
Methylation of lysine 27 on histone H3 (H3K27me), a modification associated with gene repression, plays a critical role in regulating the expression of genes that determine the balance between cell differentiation and proliferation. Alteration of the level of this histone modification has emerged as a recurrent theme in many types of cancer, demonstrating that either excess or lack of H3K27 methylation can have oncogenic effects. Cancer genome sequencing has revealed the genetic basis of H3K27me deregulation, including mutations of the components of the H3K27 methyltransferase complex PRC2 and accessory proteins, and deletions and inactivating mutations of the H3K27 demethylase UTX in a wide variety of neoplasms...
October 1, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Juliana Andrea de Oliveira Georges, Naja Vergani, Simone Aparecida Siqueira Fonseca, Ana Maria Fraga, Joana Carvalho Moreira de Mello, Maria Cecília R Maciel Albuquerque, Litsuko Shimabukuro Fujihara, Lygia Veiga Pereira
One of the differences between murine and human embryonic stem cells (ESCs) is the epigenetic state of the X chromosomes in female lines. Murine ESCs (mESCs) present two transcriptionally active Xs that will undergo the dosage compensation process of XCI upon differentiation, whereas most human ESCs (hESCs) spontaneously inactivate one X while keeping their pluripotency. Whether this reflects differences in embryonic development of mice and humans, or distinct culture requirements for the two kinds of pluripotent cells is not known...
August 2014: Stem Cell Reviews
Chunchao Zhang, Shan Gao, Anthony J Molascon, Yifan Liu, Philip C Andrews
Methylation at histone H3 lysine 27 (H3K27me) is an evolutionarily conserved epigenetic mark associated with transcriptional repression and replication elongation. We have previously shown that in Tetrahymena thermophila, a unicellular eukaryote, the histone methyltransferases (HMTs) TXR1 and EZL2 are primarily responsible for H3K27 mono-methylation (H3K27me1) and di-/tri-methylation (H3K27me2/3), respectively. Using (15)N metabolically labeled histones as the internal reference, we quantified global changes in histone post-translational modifications in ΔTXR1 and ΔEZL2 cells, to systematically identify potential crosstalk between H3K27 methylation and other PTMs across all four core histones as well as their variants...
March 2014: Molecular & Cellular Proteomics: MCP
Jun-Yuan Ji, Wayne O Miles, Michael Korenjak, Yani Zheng, Nicholas J Dyson
The E2F transcription factors are important regulators of the cell cycle whose function is commonly misregulated in cancer. To identify novel regulators of E2F1 activity in vivo, we used Drosophila to conduct genetic screens. For this, we generated transgenic lines that allow the tissue-specific depletion of dE2F1 by RNAi. Expression of these transgenes using Gal4 drivers in the eyes and wings generated reliable and modifiable phenotypes. We then conducted genetic screens testing the capacity of Exelixis deficiencies to modify these E2F1-RNAi phenotypes...
December 2012: G3: Genes—Genomes—Genetics
Yan Li, Tan Tan, Le Zong, Dacheng He, Wei Tao, Qianjin Liang
Histone methylation is one epigenetic modification of an inactive X chromosome (Xi). Histone H3 lysine 9 dimethylation (H3K9me) and histone H3 lysine 27 trimethylation (H3K27me) are both associated with the chromatin of gene-silenced regions in the X chromosome and with X inactivation. Studies have shown that H3K9me is supposedly an early mark on the X chromosome during inactivation. Here, we examined the distribution and enrichment profiles of H3K9me and H3K27me by indirect immunofluorescence. We found that H3K9me appears to have a broad distribution throughout the whole genome, but is specific, to a certain extent, to the Xi in WI38 cells...
August 2012: Chromosome Research
Yong Zheng, Liu He, Yu Wan, Jian Song
To explore the mechanisms underlying spontaneous transformation of mesenchymal stem cells (MSCs), changes in senescence-associated molecules, particularly the epigenetic modification of the p16(INK4a) gene, including histone H3 lysine 27/9 methylation (H3K27/9me) and DNA methylation, were investigated in cultured adult rat bone marrow MSCs at different stages during the transformation process. It was shown that the MSCs underwent replicative senescence after 24 to 25 population doublings, characterized by positive staining for senescence-associated β-galactosidase, increased expression of p16(INK4a) and p21, and downregulated phosphorylation of Rb...
January 15, 2013: Stem Cells and Development
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