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H3K36 methylation

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https://www.readbyqxmd.com/read/28207814/jmjd-5-kdm8-regulates-h3k36me2-and-is-required-for-late-steps-of-homologous-recombination-and-genome-integrity
#1
Pier Giorgio Amendola, Nico Zaghet, João J Ramalho, Jens Vilstrup Johansen, Mike Boxem, Anna Elisabetta Salcini
The eukaryotic genome is organized in a three-dimensional structure called chromatin, constituted by DNA and associated proteins, the majority of which are histones. Post-translational modifications of histone proteins greatly influence chromatin structure and regulate many DNA-based biological processes. Methylation of lysine 36 of histone 3 (H3K36) is a post-translational modification functionally relevant during early steps of DNA damage repair. Here, we show that the JMJD-5 regulates H3K36 di-methylation and it is required at late stages of double strand break repair mediated by homologous recombination...
February 16, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28202597/histone-lysine-to-methionine-mutations-reduce-histone-methylation-and-cause-developmental-pleiotropy
#2
Dean Sanders, Shuiming Qian, Rachael Fieweger, Li Lu, James A Dowell, John M Denu, Xuehua Zhong
Epigenetic modifications play critical roles in diverse biological processes. Histone lysine to methionine (K-to-M) mutations act as gain-of-function mutations to inhibit a wide range of histone methyltransferases and are thought to promote tumorigenesis. However, it is largely unknown whether K-to-M mutations impact development at the whole organismal level. Using Arabidopsis as a model system, we discovered that a transgene exogenously expressing histone 3 lysine 36 to methionine mutation (K36M) acts in a dominant negative manner to cause global reduction of H3K36 methylation...
February 15, 2017: Plant Physiology
https://www.readbyqxmd.com/read/28159833/setting-the-stage-for-cancer-development-setd2-and-the-consequences-of-lost-methylation
#3
Catherine C Fahey, Ian J Davis
The H3 lysine 36 histone methyltransferase SETD2 is mutated across a range of human cancers. Although other enzymes can mediate mono- and dimethylation, SETD2 is the exclusive trimethylase. SETD2 associates with the phosphorylated carboxy-terminal domain of RNA polymerase and modifies histones at actively transcribed genes. The functions associated with SETD2 are mediated through multiple effector proteins that bind trimethylated H3K36. These effectors directly mediate multiple chromatin-regulated processes, including RNA splicing, DNA damage repair, and DNA methylation...
February 3, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28129023/probe-the-function-of-histone-lysine-36-methylation-using-histone-h3-lysine-36-to-methionine-mutant-transgene-in-mammalian-cells
#4
Dong Fang, Haiyun Gan, Heping Wang, Hui Zhou, Zhiguo Zhang
Chondroblastoma is a cartilaginous tumor that typically arises under 25 years of age (80%). Recent studies have identified a somatic and heterozygous mutation at the H3F3B gene in over 90% chondroblastoma cases, leading to a lysine 36 to methionine replacement (H3.3K36M). In human cells, H3F3B gene is one of two genes that encode identical H3.3 proteins. It is not known how H3.3K36M mutant proteins promote tumorigenesis. We and others have shown that, the levels of H3K36 di- and tri-methylation (H3K36me2/me3) are reduced dramatically in chondroblastomas and chondrocytes bearing the H3...
January 27, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28108585/histone-h3k4-and-h3k36-methylation-independently-recruit-the-nua3-histone-acetyltransferase-in-saccharomyces-cerevisiae
#5
Benjamin J E Martin, Kristina L McBurney, Vicki E Maltby, Kristoffer N Jensen, Julie Brind'Amour, LeAnn Howe
Histone post-translational modifications (PTMs) alter chromatin structure by promoting the interaction of chromatin-modifying complexes with nucleosomes. The majority of chromatin-modifying complexes contain multiple domains that preferentially interact with modified histones, leading to speculation that these domains function in concert to target nucleosomes with distinct combinations of histone PTMs. In S. cerevisiae, the NuA3 histone acetyltransferase complex contains three domains, the PHD finger in Yng1, the PWWP domain in Pdp3, and the YEATS domain in Taf14, which in vitro bind to H3K4 methylation, H3K36 methylation, and acetylated and crotonylated H3K9 respectively...
January 20, 2017: Genetics
https://www.readbyqxmd.com/read/28067913/impaired-h3k36-methylation-defines-a-subset-of-head-and-neck-squamous-cell-carcinomas
#6
Simon Papillon-Cavanagh, Chao Lu, Tenzin Gayden, Leonie G Mikael, Denise Bechet, Christina Karamboulas, Laurie Ailles, Jason Karamchandani, Dylan M Marchione, Benjamin A Garcia, Ilan Weinreb, David Goldstein, Peter W Lewis, Octavia Maria Dancu, Sandeep Dhaliwal, William Stecho, Christopher J Howlett, Joe S Mymryk, John W Barrett, Anthony C Nichols, C David Allis, Jacek Majewski, Nada Jabado
Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) are deadly and common cancers. Recent genomic studies implicate multiple genetic pathways, including cell signaling, cell cycle and immune evasion, in their development. Here we analyze public data sets and uncover a previously unappreciated role of epigenome deregulation in the genesis of 13% of HPV-negative HNSCCs. Specifically, we identify novel recurrent mutations encoding p.Lys36Met (K36M) alterations in multiple H3 histone genes...
January 9, 2017: Nature Genetics
https://www.readbyqxmd.com/read/27892458/modulation-of-mrna-and-lncrna-expression-dynamics-by-the-set2-rpd3s-pathway
#7
Ji Hyun Kim, Bo Bae Lee, Young Mi Oh, Chenchen Zhu, Lars M Steinmetz, Yookyeong Lee, Wan Kyu Kim, Sung Bae Lee, Stephen Buratowski, TaeSoo Kim
H3K36 methylation by Set2 targets Rpd3S histone deacetylase to transcribed regions of mRNA genes, repressing internal cryptic promoters and slowing elongation. Here we explore the function of this pathway by analysing transcription in yeast undergoing a series of carbon source shifts. Approximately 80 mRNA genes show increased induction upon SET2 deletion. A majority of these promoters have overlapping lncRNA transcription that targets H3K36me3 and deacetylation by Rpd3S to the mRNA promoter. We previously reported a similar mechanism for H3K4me2-mediated repression via recruitment of the Set3C histone deacetylase...
November 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27892455/selective-suppression-of-antisense-transcription-by-set2-mediated-h3k36-methylation
#8
Swaminathan Venkatesh, Hua Li, Madelaine M Gogol, Jerry L Workman
Maintenance of a regular chromatin structure over the coding regions of genes occurs co-transcriptionally via the 'chromatin resetting' pathway. One of the central players in this pathway is the histone methyltransferase Set2. Here we show that the loss of Set2 in yeast, Saccharomyces cerevisiae, results in transcription initiation of antisense RNAs embedded within body of protein-coding genes. These RNAs are distinct from the previously identified non-coding RNAs and cover 11% of the yeast genome. These RNA species have been named Set2-repressed antisense transcripts (SRATs) since the co-transcriptional addition of the H3K36 methyl mark by Set2 over their start sites results in their suppression...
November 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27791097/stable-caenorhabditis-elegans-chromatin-domains-separate-broadly-expressed-and-developmentally-regulated-genes
#9
Kenneth J Evans, Ni Huang, Przemyslaw Stempor, Michael A Chesney, Thomas A Down, Julie Ahringer
Eukaryotic genomes are organized into domains of differing structure and activity. There is evidence that the domain organization of the genome regulates its activity, yet our understanding of domain properties and the factors that influence their formation is poor. Here, we use chromatin state analyses in early embryos and third-larval stage (L3) animals to investigate genome domain organization and its regulation in Caenorhabditis elegans At both stages we find that the genome is organized into extended chromatin domains of high or low gene activity defined by different subsets of states, and enriched for H3K36me3 or H3K27me3, respectively...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27723431/h3k36-methylation-state-and-associated-silencing-mechanisms
#10
Shota Suzuki, Yota Murakami, Shinya Takahata
Epigenetic marks determine cell fate via numerous reader proteins. H3K36 methylation is a common epigenetic mark that is thought to be associated with the activities of the RNA polymerase 2 C-terminal domain. We discuss a novel silencing mechanism regulated by Set2-dependent H3K36 methylation that involves exosome-dependent RNA processing.
January 2017: Transcription
https://www.readbyqxmd.com/read/27694114/epigenetic-control-of-phenotypic-plasticity-in-the-filamentous-fungus-neurospora-crassa
#11
Ilkka Kronholm, Hanna Johannesson, Tarmo Ketola
Phenotypic plasticity is the ability of a genotype to produce different phenotypes under different environmental or developmental conditions. Phenotypic plasticity is a ubiquitous feature of living organisms, and is typically based on variable patterns of gene expression. However, the mechanisms by which gene expression is influenced and regulated during plastic responses are poorly understood in most organisms. While modifications to DNA and histone proteins have been implicated as likely candidates for generating and regulating phenotypic plasticity, specific details of each modification and its mode of operation have remained largely unknown...
December 7, 2016: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/27573846/mrg15-is-required-for-pre-mrna-splicing-and-spermatogenesis
#12
Naoki Iwamori, Kaoru Tominaga, Tetsuya Sato, Kevin Riehle, Tokuko Iwamori, Yasuyuki Ohkawa, Cristian Coarfa, Etsuro Ono, Martin M Matzuk
Splicing can be epigenetically regulated and involved in cellular differentiation in somatic cells, but the interplay of epigenetic factors and the splicing machinery during spermatogenesis remains unclear. To study these interactions in vivo, we generated a germline deletion of MORF-related gene on chromosome 15 (MRG15), a multifunctional chromatin organizer that binds to methylated histone H3 lysine 36 (H3K36) in introns of transcriptionally active genes and has been implicated in regulation of histone acetylation, homology-directed DNA repair, and alternative splicing in somatic cells...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27548565/h3k36-methyltransferases-as-cancer-drug-targets-rationale-and-perspectives-for-inhibitor-development
#13
David S Rogawski, Jolanta Grembecka, Tomasz Cierpicki
Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors...
September 2016: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/27535225/the-eaf3-5-7-subcomplex-stimulates-nua4-interaction-with-methylated-histone-h3-lys-36-and-rna-polymerase-ii
#14
Anish Sathianathan, Priyadarshini Ravichandran, Jake M Lippi, Leah Cohen, Angelo Messina, Sherwin Shaju, Marci J Swede, Daniel S Ginsburg
NuA4 is the only essential lysine acetyltransferase complex in Saccharomyces cerevisiae, where it has been shown to stimulate transcription initiation and elongation. Interaction with nucleosomes is stimulated by histone H3 Lys-4 and Lys-36 methylation, but the mechanism of this interaction is unknown. Eaf3, Eaf5, and Eaf7 form a subcomplex within NuA4 that may also function independently of the lysine acetyltransferase complex. The Eaf3/5/7 complex and the Rpd3C(S) histone deacetylase complex have both been shown to bind di- and trimethylated histone H3 Lys-36 stimulated by Eaf3...
September 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27505861/4-biphenylalanine-and-3-phenyltyrosine-derived-hydroxamic-acids-as-inhibitors-of-the-jumonjic-domain-containing-histone-demethylase-kdm4a
#15
Ludovica Morera, Martin Roatsch, Michael C D Fürst, Inga Hoffmann, Johanna Senger, Mirjam Hau, Henriette Franz, Roland Schüle, Markus R Heinrich, Manfred Jung
Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50 value of 25.4 μm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs...
September 20, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27354553/global-regulation-of-plant-immunity-by-histone-lysine-methyl-transferases
#16
Sanghun Lee, Fuyou Fu, Siming Xu, Sang Yeol Lee, Dae-Jin Yun, Tesfaye Mengiste
Posttranslational modification of histones modulates gene expression affecting diverse biological functions. We showed that the Arabidopsis thaliana histone methyl transferases SET DOMAIN GROUP8 (SDG8) and SDG25 regulate pep1-, flg22-, and effector-triggered immunity as well as systemic acquired resistance. Genome-wide basal and induced transcriptome changes regulated by SDG8 and/or SDG25 showed that two genes of the SDG-dependent transcriptome, CAROTENOID ISOMERASE2 (CCR2) and ECERIFERUM3 (CER3), were also required for plant immunity, establishing mechanisms in defense functions for SDG8 and SDG25...
July 2016: Plant Cell
https://www.readbyqxmd.com/read/27268234/both-h4k20-mono-methylation-and-h3k56-acetylation-mark-transcription-dependent-histone-turnover-in-fission-yeast
#17
Hanna Yang, Chang Seob Kwon, Yoonjung Choi, Daeyoup Lee
Nucleosome dynamics facilitated by histone turnover is required for transcription as well as DNA replication and repair. Histone turnover is often associated with various histone modifications such as H3K56 acetylation (H3K56Ac), H3K36 methylation (H3K36me), and H4K20 methylation (H4K20me). In order to correlate histone modifications and transcription-dependent histone turnover, we performed genome wide analyses for euchromatic regions in G2/M-arrested fission yeast. The results show that transcription-dependent histone turnover at 5' promoter and 3' termination regions is directly correlated with the occurrence of H3K56Ac and H4K20 mono-methylation (H4K20me1) in actively transcribed genes...
August 5, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27266524/continual-removal-of-h3k9-promoter-methylation-by-jmjd2-demethylases-is-vital-for-esc-self-renewal-and-early-development
#18
Marianne Terndrup Pedersen, Susanne Marije Kooistra, Aliaksandra Radzisheuskaya, Anne Laugesen, Jens Vilstrup Johansen, Daniel Geoffrey Hayward, Jakob Nilsson, Karl Agger, Kristian Helin
Chromatin-associated proteins are essential for the specification and maintenance of cell identity. They exert these functions through modulating and maintaining transcriptional patterns. To elucidate the functions of the Jmjd2 family of H3K9/H3K36 histone demethylases, we generated conditional Jmjd2a/Kdm4a, Jmjd2b/Kdm4b and Jmjd2c/Kdm4c/Gasc1 single, double and triple knockout mouse embryonic stem cells (ESCs). We report that while individual Jmjd2 family members are dispensable for ESC maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired ESC self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions...
July 15, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27249350/coupling-of-histone-methylation-and-rna-processing-by-the-nuclear-mrna-cap-binding-complex
#19
Zicong Li, Danhua Jiang, Xing Fu, Xiao Luo, Renyi Liu, Yuehui He
In eukaryotes, genes are transcribed into pre-mRNAs that are subsequently processed into mature mRNAs by adding a 5'-cap and a 3'-polyA tail and splicing introns. Pre-mRNA processing involves their binding proteins and processing factors, whereas gene transcription often involves chromatin modifiers. It has been unclear how the factors involved in chromatin modifications and RNA processing function in concert to control mRNA production. Here, we show that in Arabidopsis thaliana, the evolutionarily conserved nuclear mRNA cap-binding complex (CBC) forms multi-protein complexes with a conserved histone 3 lysine 4 (H3K4) methyltransferase complex called COMPASS-like and a histone 3 lysine 36 (H3K36) methyltransferase to integrate active histone methylations with co-transcriptional mRNA processing and cap preservation, leading to a high level of mature mRNA production...
2016: Nature Plants
https://www.readbyqxmd.com/read/27229140/the-histone-h3-3k36m-mutation-reprograms-the-epigenome-of-chondroblastomas
#20
Dong Fang, Haiyun Gan, Jeong-Heon Lee, Jing Han, Zhiquan Wang, Scott M Riester, Long Jin, Jianji Chen, Hui Zhou, Jinglong Wang, Honglian Zhang, Na Yang, Elizabeth W Bradley, Thai H Ho, Brian P Rubin, Julia A Bridge, Stephen N Thibodeau, Tamas Ordog, Yue Chen, Andre J van Wijnen, Andre M Oliveira, Rui-Ming Xu, Jennifer J Westendorf, Zhiguo Zhang
More than 90% of chondroblastomas contain a heterozygous mutation replacing lysine-36 with methionine-36 (K36M) in the histone H3 variant H3.3. Here we show that H3K36 methylation is reduced globally in human chondroblastomas and in chondrocytes harboring the same genetic mutation, due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and trimethylation in H3.3K36M cells are enriched in cancer pathways...
June 10, 2016: Science
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