Genomes and Genes
histone lysine n methyltransferase
Summary: An enzyme that catalyzes the methylation of the epsilon-amino group of lysine residues in proteins to yield epsilon mono-, di-, and trimethyllysine. EC 188.8.131.52.
- Jørgensen S, Elvers I, Trelle M, Menzel T, Eskildsen M, Jensen O, et al. The histone methyltransferase SET8 is required for S-phase progression. J Cell Biol. 2007;179:1337-45 pubmed publisher..Overall, we show that SET8 is essential for genomic stability in mammalian cells and that decreased expression of SET8 results in DNA damage and Chk1-dependent S-phase arrest. ..
- Chang Y, Zhang X, Horton J, Upadhyay A, Spannhoff A, Liu J, et al. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol. 2009;16:312-7 pubmed publisher..The inhibitor resembles the bound conformation of histone H3 Lys4 to Arg8, and is positioned in place by residues specific for G9a and GLP through specific interactions. ..
- Parvanov E, Petkov P, Paigen K. Prdm9 controls activation of mammalian recombination hotspots. Science. 2010;327:835 pubmed publisher..The identification of Prdm9 as a protein regulating mammalian recombination hotspots initiates molecular studies of this important biological control system. ..
- Baudat F, Buard J, Grey C, Fledel Alon A, Ober C, Przeworski M, et al. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science. 2010;327:836-40 pubmed publisher..Our results provide a molecular basis for the distribution of meiotic recombination in mammals, in which the binding of PRDM9 to specific DNA sequences targets the initiation of recombination at specific locations in the genome. ..
- Li B, Jackson J, Simon M, Fleharty B, Gogol M, Seidel C, et al. Histone H3 lysine 36 dimethylation (H3K36me2) is sufficient to recruit the Rpd3s histone deacetylase complex and to repress spurious transcription. J Biol Chem. 2009;284:7970-6 pubmed publisher..Transcription analysis and genome-wide histone modification studies on these mutants suggested that K36me2 is sufficient to target Rpd3S in vivo, thereby maintaining a functional Set2-Rpd3S pathway. ..
- Wray J, Williamson E, Sheema S, Lee S, Libby E, Willman C, et al. Metnase mediates chromosome decatenation in acute leukemia cells. Blood. 2009;114:1852-8 pubmed publisher..Thus, Metnase expression levels may predict AML resistance to Topo IIalpha inhibitors, and Metnase is a potential therapeutic target for small molecule interference. ..
- Houston S, McManus K, Adams M, Sims J, Carpenter P, Hendzel M, et al. Catalytic function of the PR-Set7 histone H4 lysine 20 monomethyltransferase is essential for mitotic entry and genomic stability. J Biol Chem. 2008;283:19478-88 pubmed publisher..Our results predict that alterations of this pathway could result in gross chromosomal aberrations and aneuploidy. ..
- Williamson E, Rasila K, Corwin L, Wray J, Beck B, Severns V, et al. The SET and transposase domain protein Metnase enhances chromosome decatenation: regulation by automethylation. Nucleic Acids Res. 2008;36:5822-31 pubmed publisher..Thus, Metnase enhances Topo IIalpha decatenation, and this activity is repressed by automethylation. These results suggest that cancer cells could subvert Metnase to mediate clinically relevant resistance to Topo IIalpha inhibitors. ..
- Wong C, Tellam R. MicroRNA-26a targets the histone methyltransferase Enhancer of Zeste homolog 2 during myogenesis. J Biol Chem. 2008;283:9836-43 pubmed publisher..These results reveal a model of regulation during myogenesis whereby the up-regulation of miR-26a acts to post-transcriptionally repress Ezh2, a known suppressor of skeletal muscle cell differentiation. ..
- Rathert P, Zhang X, Freund C, Cheng X, Jeltsch A. Analysis of the substrate specificity of the Dim-5 histone lysine methyltransferase using peptide arrays. Chem Biol. 2008;15:5-11 pubmed publisher..Comparative analyses of peptide arrays with wild-type and mutant enzymes, therefore, are well suited to investigate the target specificity of protein methyltransferases and study epigenetic crosstalk. ..
- Yasuhara J, Wakimoto B. Molecular landscape of modified histones in Drosophila heterochromatic genes and euchromatin-heterochromatin transition zones. PLoS Genet. 2008;4:e16 pubmed publisher..The results are also relevant for understanding the effects of chromosome aberrations and the megabase scale over which epigenetic position effects can operate in multicellular organisms. ..
- Venkatasubrahmanyam S, Hwang W, Meneghini M, Tong A, Madhani H. Genome-wide, as opposed to local, antisilencing is mediated redundantly by the euchromatic factors Set1 and H2A.Z. Proc Natl Acad Sci U S A. 2007;104:16609-14 pubmed..Antisilencing mechanisms may therefore cooperate to play a considerably broader role in regulating genome-wide transcription than previously thought. ..
- Kim J, Kee H, Choe N, Kim S, Eom G, Baek H, et al. Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. Mol Cell Biol. 2008;28:2023-34 pubmed publisher..These data illustrate the important regulatory role of RE-IIBP in transcriptional regulation, thereby pointing to the important role of HMTase activity in carcinogenesis. ..
- Tachibana M, Matsumura Y, Fukuda M, Kimura H, Shinkai Y. G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. EMBO J. 2008;27:2681-90 pubmed publisher..This is the first clear evidence that G9a/GLP suppresses transcription by independently inducing both H3K9 and DNA methylation. ..
- Oda H, Okamoto I, Murphy N, Chu J, Price S, Shen M, et al. Monomethylation of histone H4-lysine 20 is involved in chromosome structure and stability and is essential for mouse development. Mol Cell Biol. 2009;29:2278-95 pubmed publisher..Most importantly, the lack of H4K20me1 also resulted in defects in chromosome condensation in interphase nuclei. These results demonstrate the critical role of H4K20 monomethylation in mammals in a developmental context. ..
- Pless O, Kowenz Leutz E, Knoblich M, Lausen J, Beyermann M, Walsh M, et al. G9a-mediated lysine methylation alters the function of CCAAT/enhancer-binding protein-beta. J Biol Chem. 2008;283:26357-63 pubmed publisher..Our data identify C/EBPbeta as a direct substrate of G9a-mediated post-translational modification that alters the functional properties of C/EBPbeta during gene regulation. ..
- Roman Y, Oshige M, Lee Y, Goodwin K, Georgiadis M, Hromas R, et al. Biochemical characterization of a SET and transposase fusion protein, Metnase: its DNA binding and DNA cleavage activity. Biochemistry. 2007;46:11369-76 pubmed..Together, our results suggest that Metnase's DNA cleavage activity, unlike those of other eukaryotic transposases, is not coupled to its sequence-specific DNA binding. ..
- Sher F, Rössler R, Brouwer N, Balasubramaniyan V, Boddeke E, Copray S. Differentiation of neural stem cells into oligodendrocytes: involvement of the polycomb group protein Ezh2. Stem Cells. 2008;26:2875-83 pubmed publisher..Disclosure of potential conflicts of interest is found at the end of this article. ..
- Zou J, Wang S, Yang J, Luo X, Xie J, Xi T. Knockdown of SMYD3 by RNA interference down-regulates c-Met expression and inhibits cells migration and invasion induced by HGF. Cancer Lett. 2009;280:78-85 pubmed publisher..The present findings provide significant insights into the epigenetic regulatory mechanisms of oncogene c-Met expression, and develop the strategies that may inhibit the progression of cancer migration and invasion. ..
- Yuan W, Xie J, Long C, Erdjument Bromage H, Ding X, Zheng Y, et al. Heterogeneous nuclear ribonucleoprotein L Is a subunit of human KMT3a/Set2 complex required for H3 Lys-36 trimethylation activity in vivo. J Biol Chem. 2009;284:15701-7 pubmed publisher..Moreover, KMT3a generates mono-, di-, and trimethylated products in vitro, but RNA interference against KMT3a or HnRNP-L down-regulates exclusively the H3K36me3 mark in vivo. ..
- Miller S, Huang A, Miazgowicz M, Brassil M, Weinmann A. Coordinated but physically separable interaction with H3K27-demethylase and H3K4-methyltransferase activities are required for T-box protein-mediated activation of developmental gene expression. Genes Dev. 2008;22:2980-93 pubmed publisher..These novel mechanisms for T-box-mediated epigenetic regulation are essential, because point mutations that disrupt these interactions are found in a diverse array of human developmental genetic diseases. ..
- Chaturvedi C, Hosey A, Palii C, Perez Iratxeta C, Nakatani Y, Ranish J, et al. Dual role for the methyltransferase G9a in the maintenance of beta-globin gene transcription in adult erythroid cells. Proc Natl Acad Sci U S A. 2009;106:18303-8 pubmed publisher..Collectively, these results reveal a dual role for G9a in maintaining proper expression (both repression and activation) of the beta-globin genes in differentiating adult erythroid cells...
- Frederiks F, Tzouros M, Oudgenoeg G, van Welsem T, Fornerod M, Krijgsveld J, et al. Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states. Nat Struct Mol Biol. 2008;15:550-7 pubmed publisher..Our results suggest that multiple methylation of H3K79 leads to a binary code, which is expected to limit the possibilities for regulation by putative demethylases or binding proteins. ..
- Pesavento J, Yang H, Kelleher N, Mizzen C. Certain and progressive methylation of histone H4 at lysine 20 during the cell cycle. Mol Cell Biol. 2008;28:468-86 pubmed..Together, our data provide an unbiased perspective of the regulation and function of K20 methylation. ..
- Wang S, Luo X, Shen J, Zou J, Lu Y, Xi T. Knockdown of SMYD3 by RNA interference inhibits cervical carcinoma cell growth and invasion in vitro. BMB Rep. 2008;41:294-9 pubmed..These findings imply that SMYD3 plays crucial roles in HeLa cell proliferation and migration/invasion, and that it may be a useful therapeutic target in human cervical carcinomas. ..
- Couture J, Dirk L, Brunzelle J, Houtz R, Trievel R. Structural origins for the product specificity of SET domain protein methyltransferases. Proc Natl Acad Sci U S A. 2008;105:20659-64 pubmed publisher..Collectively, these results indicate that the Phe/Tyr switch regulates product specificity through altering the affinity of an active-site water molecule whose dissociation is required for lysine multiple methylation. ..
- Spannhoff A, Hauser A, Heinke R, Sippl W, Jung M. The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. ChemMedChem. 2009;4:1568-82 pubmed publisher..Special emphasis is placed on the strategies that led to the first inhibitors which are currently available and the screening approaches that were used in that process. ..
- Yokochi T, Poduch K, Ryba T, Lu J, Hiratani I, Tachibana M, et al. G9a selectively represses a class of late-replicating genes at the nuclear periphery. Proc Natl Acad Sci U S A. 2009;106:19363-8 pubmed publisher..We conclude that G9a is a gatekeeper for a specific set of genes localized within the late replicating nuclear periphery. ..
- Lee J, Shukla A, Schneider J, Swanson S, Washburn M, Florens L, et al. Histone crosstalk between H2B monoubiquitination and H3 methylation mediated by COMPASS. Cell. 2007;131:1084-96 pubmed..Cps35 is also required for proper H3K79 trimethylation. These findings offer insight into the molecular role of Cps35 in translating the H2B monoubiquitination signal into H3 methylation. ..
- Tan C, Sindhu K, Li S, Nishio H, Stoller J, Oishi K, et al. Transcription factor Ap2delta associates with Ash2l and ALR, a trithorax family histone methyltransferase, to activate Hoxc8 transcription. Proc Natl Acad Sci U S A. 2008;105:7472-7 pubmed publisher..This role provides a mechanism through which these transcription factors can have diverse effects despite nearly identical DNA-binding motifs. ..
- Williamson E, Farrington J, Martinez L, Ness S, O Rourke J, Lee S, et al. Expression levels of the human DNA repair protein metnase influence lentiviral genomic integration. Biochimie. 2008;90:1422-6 pubmed publisher..While Metnase levels affected lentiviral integration, it had no effect on the amount of either total cellular viral RNA, cDNA or 2-LTR circles. Therefore, Metnase enhances the integration of lentivirus DNA into the host cell genome. ..
- Li Y, Reddy M, Miao F, Shanmugam N, Yee J, Hawkins D, et al. Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes. Relevance to diabetes and inflammation. J Biol Chem. 2008;283:26771-81 pubmed publisher..These results demonstrate a novel role for SET7/9 in inflammation and diabetes. ..
- Schotta G, Sengupta R, Kubicek S, Malin S, Kauer M, Callen E, et al. A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev. 2008;22:2048-61 pubmed publisher..Thus, conversion to an H4K20me1 state results in compromised chromatin that is insufficient to protect genome integrity and to process a DNA-rearranging differentiation program in the mouse. ..
- Kim J, Guermah M, McGinty R, Lee J, Tang Z, Milne T, et al. RAD6-Mediated transcription-coupled H2B ubiquitylation directly stimulates H3K4 methylation in human cells. Cell. 2009;137:459-71 pubmed publisher..These studies establish the natural H2B ubiquitylation factors in human cells and also detail the mechanistic basis for H2B ubiquitylation and function during transcription. ..
- Myers S, Bowden R, Tumian A, Bontrop R, Freeman C, MacFie T, et al. Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science. 2010;327:876-9 pubmed publisher..The involvement of PRDM9, which causes histone H3 lysine 4 trimethylation, implies that there is a common mechanism for recombination hotspots in eukaryotes but raises questions about what forces have driven such rapid change. ..
- Ma D, Chiang C, Ponnusamy K, Ming G, Song H. G9a and Jhdm2a regulate embryonic stem cell fusion-induced reprogramming of adult neural stem cells. Stem Cells. 2008;26:2131-41 pubmed publisher..These mechanistic findings may guide more efficient reprogramming for future therapeutic applications of stem cells. Disclosure of potential conflicts of interest is found at the end of this article. ..
- Xu Z, Gong Q, Xia B, Groves B, Zimmermann M, Mugler C, et al. A role of histone H3 lysine 4 methyltransferase components in endosomal trafficking. J Cell Biol. 2009;186:343-53 pubmed publisher..Collectively, these results suggest that mDpy-30 and probably H3K4MT play a role in the endosomal transport of specific cargo proteins. ..
- Bell O, Wirbelauer C, Hild M, Scharf A, Schwaiger M, MacAlpine D, et al. Localized H3K36 methylation states define histone H4K16 acetylation during transcriptional elongation in Drosophila. EMBO J. 2007;26:4974-84 pubmed..Thus di- and trimethylation of H3K36 have opposite effects on H4K16 acetylation, which we propose enable dynamic changes in chromatin compaction during transcript elongation. ..
- Jones B, Su H, Bhat A, Lei H, Bajko J, Hevi S, et al. The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure. PLoS Genet. 2008;4:e1000190 pubmed publisher..Taken together, these results indicate that Dot1L and H3K79 methylation play important roles in heterochromatin formation and in embryonic development. ..
- Shirato H, Ogawa S, Nakajima K, Inagawa M, Kojima M, Tachibana M, et al. A jumonji (Jarid2) protein complex represses cyclin D1 expression by methylation of histone H3-K9. J Biol Chem. 2009;284:733-9 pubmed publisher..These results suggest that Jmj methylates H3-K9 and represses cyclin D1 expression through G9a and GLP, and that Jmj family proteins can regulate gene expression by not only histone demethylation but also other histone modification. ..
- Wen B, Wu H, Shinkai Y, Irizarry R, Feinberg A. Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nat Genet. 2009;41:246-50 pubmed publisher..We term these regions large organized chromatin K9 modifications (LOCKs). LOCKs are substantially lost in cancer cell lines, and they may provide a cell type-heritable mechanism for phenotypic plasticity in development and disease. ..
- Kang H, Choi Y, Lee J, Choi K, Kim H, Yoo J, et al. The histone methyltransferase, NSD2, enhances androgen receptor-mediated transcription. FEBS Lett. 2009;583:1880-6 pubmed publisher..Taken together, these results uncover a potential role for NSD2 in AR-mediated transcription, implicating NSD2 in prostate carcinogenesis. ..
- Ramon Maiques S, Kuo A, Carney D, Matthews A, Oettinger M, Gozani O, et al. The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2. Proc Natl Acad Sci U S A. 2007;104:18993-8 pubmed
- Oliver P, Goodstadt L, Bayes J, Birtle Z, Roach K, Phadnis N, et al. Accelerated evolution of the Prdm9 speciation gene across diverse metazoan taxa. PLoS Genet. 2009;5:e1000753 pubmed publisher..We suggest that Prdm9 should be investigated as a candidate gene in other instances of hybrid sterility in metazoans...
- Cazzonelli C, Cuttriss A, Cossetto S, Pye W, Crisp P, Whelan J, et al. Regulation of carotenoid composition and shoot branching in Arabidopsis by a chromatin modifying histone methyltransferase, SDG8. Plant Cell. 2009;21:39-53 pubmed publisher..Thus, the level of lutein, the most abundant carotenoid in higher plants that is critical for photosynthesis and photoprotection, appears to be regulated by a chromatin modifying enzyme in Arabidopsis thaliana. ..
- Marango J, Shimoyama M, Nishio H, Meyer J, Min D, Sirulnik A, et al. The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood. 2008;111:3145-54 pubmed