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H3K36 methylation

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.
October 10, 2016: Transcription
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 an 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...
September 30, 2016: G3: Genes—Genomes—Genetics
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
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
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
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
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
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
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
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
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
Yongcan Chen, Wei-Guo Zhu
DNA damage response (DDR) signaling network is initiated to protect cells from various exogenous and endogenous damage resources. Timely and accurate regulation of DDR proteins is required for distinct DNA damage repair pathways. Post-translational modifications of histone and non-histone proteins play a vital role in the DDR factor foci formation and signaling pathway. Phosphorylation, ubiquitylation, SUMOylation, neddylation, poly(ADP-ribosyl)ation, acetylation, and methylation are all involved in the spatial-temporal regulation of DDR, among which phosphorylation and ubiquitylation are well studied...
July 2016: Acta Biochimica et Biophysica Sinica
(no author information available yet)
H3K36M-mutant histones prevent mesenchymal progenitor cell differentiation and induce sarcoma.
July 2016: Cancer Discovery
Myles B Poulin, Jessica L Schneck, Rosalie E Matico, Wangfang Hou, Patrick J McDevitt, Marc Holbert, Vern L Schramm
Nuclear receptor-binding SET domain protein 2 (NSD2) is a histone H3 lysine 36 (H3K36)-specific methyltransferase enzyme that is overexpressed in a number of cancers, including multiple myeloma. NSD2 binds to S-adenosyl-l-methionine (SAM) and nucleosome substrates to catalyze the transfer of a methyl group from SAM to the ε-amino group of histone H3K36. Equilibrium binding isotope effects and density functional theory calculations indicate that the SAM methyl group is sterically constrained in complex with NSD2, and that this steric constraint is released upon nucleosome binding...
June 1, 2016: Journal of the American Chemical Society
Chao Lu, Siddhant U Jain, Dominik Hoelper, Denise Bechet, Rosalynn C Molden, Leili Ran, Devan Murphy, Sriram Venneti, Meera Hameed, Bruce R Pawel, Jay S Wunder, Brendan C Dickson, Stefan M Lundgren, Krupa S Jani, Nicolas De Jay, Simon Papillon-Cavanagh, Irene L Andrulis, Sarah L Sawyer, David Grynspan, Robert E Turcotte, Javad Nadaf, Somayyeh Fahiminiyah, Tom W Muir, Jacek Majewski, Craig B Thompson, Ping Chi, Benjamin A Garcia, C David Allis, Nada Jabado, Peter W Lewis
Several types of pediatric cancers reportedly contain high-frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here we report that the H3 lysine 36-to-methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation...
May 13, 2016: Science
Junjian Wang, Zhijian Duan, Zoann Nugent, June X Zou, Alexander D Borowsky, Yanhong Zhang, Clifford G Tepper, Jian Jian Li, Oliver Fiehn, Jianzhen Xu, Hsing-Jien Kung, Leigh C Murphy, Hong-Wu Chen
Metabolic reprogramming such as the aerobic glycolysis or Warburg effect is well recognized as a common feature of tumorigenesis. However, molecular mechanisms underlying metabolic alterations for tumor therapeutic resistance are poorly understood. Through gene expression profiling analysis we found that histone H3K36 methyltransferase NSD2/MMSET/WHSC1 expression was highly elevated in tamoxifen-resistant breast cancer cell lines and clinical tumors. IHC analysis indicated that NSD2 protein overexpression was associated with the disease recurrence and poor survival...
May 6, 2016: Cancer Letters
Levi L Blazer, Evelyne Lima-Fernandes, Elisa Gibson, Mohammad S Eram, Peter Loppnau, Cheryl H Arrowsmith, Matthieu Schapira, Masoud Vedadi
PR domain-containing protein 7 (PRDM7) is a primate-specific histone methyltransferase that is the result of a recent gene duplication of PRDM9. The two proteins are highly homologous, especially in the catalytic PR/SET domain, where they differ by only three amino acid residues. Here we report that PRDM7 is an efficient methyltransferase that selectively catalyzes the trimethylation of H3 lysine 4 (H3K4) both in vitro and in cells. Through selective mutagenesis we have dissected the functional roles of each of the three divergent residues between the PR domains of PRDM7 and PRDM9...
June 24, 2016: Journal of Biological Chemistry
Guoxia Yu, Jinsong Wang, Xiao Lin, Shu Diao, Yu Cao, Rui Dong, Liping Wang, Songlin Wang, Zhipeng Fan
OBJECTIVES: Dental mesenchymal stem cells (MSCs) are easily obtained; however, mechanisms underlying directed differentiation of these cells remains unclear. Wnt/β-catenin signalling is essential for mesenchymal cell commitment and differentiation, and Wnt inhibition is linked to stem cell maintenance and function. Secreted frizzled-related protein 2 (SFRP2) competes with the Frizzled receptor for direct binding to Wnt and blocks activation of Wnt signalling. Here, we used stem cells derived from apical papillae (SCAPs) to study the functions of SFRP2...
June 2016: Cell Proliferation
Jing-Yi Chen, Chien-Feng Li, Pei-Yi Chu, You-Syuan Lai, Chung-Hsing Chen, Shih Sheng Jiang, Ming-Feng Hou, Wen-Chun Hung
Alterations of histone methylation dynamically regulated by methyltransferases and demethylases are frequently found in human cancers. Here, we showed that expression of lysine demethylase 2A (KDM2A) is markedly increased in human breast cancer and its overexpression is associated with tumor progression and poor prognosis. Knockdown of KDM2A in breast cancer cells reduced proliferation but not viability. Gene set enrichment analysis revealed that inhibition of KDM2A down-regulates angiogenic genes with concurrent reduction of Jagged1 (JAG1), NOTCH1 and HEY1 in the NOTCH signaling...
May 10, 2016: Oncotarget
Guangyan Sun, Zhipeng Zhou, Xiao Liu, Kexin Gai, Qingqing Liu, Joonseok Cha, Farah Naz Kaleri, Ying Wang, Qun He
The circadian system in Neurospora is based on the transcriptional/translational feedback loops and rhythmic frequency (frq) transcription requires the WHITE COLLAR (WC) complex. Our previous paper has shown that frq could be transcribed in a WC-independent pathway in a strain lacking the histone H3K36 methyltransferase, SET-2 (su(var)3-9-enhancer-of-zeste-trithorax-2) (1), but the mechanism was unclear. Here we disclose that loss of histone H3K36 methylation, due to either deletion of SET-2 or H3K36R mutation, results in arrhythmic frq transcription and loss of overt rhythmicity...
May 20, 2016: Journal of Biological Chemistry
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