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G9a and G9a-Like Histone Methyltransferases and Their Effect on Cell Phenotype, Embryonic Development, and Human Disease

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The DNA, RNA, and Histone Methylomes

Part of the book series: RNA Technologies ((RNATECHN))

Abstract

Post-translational modifications of histone proteins alter the topology of the chromatin, which affect genome accessibility and thus, impact gene regulation. One type of histone modification that has a profound effect on the chromatin is methylation, where specific marking of lysine or arginine residues within the N-terminal tails of the histone core proteins control chromatin packaging and transcriptional dynamics throughout the genome. Two important histone methyltransferases are G9a and G9a-like protein-1 (GLP), whose enzymatic activities have a major influence on cell phenotype, embryonic development, cancer progression, and other human diseases. This review will provide an overview of the structural and enzymatic properties of G9a and GLP, the development of pharmacological reagents that target their catalytic activities, the impact of these enzymes on cell biology, embryogenesis, cancer progression, neurological and other human diseases. In addition, we will examine the known non-histone targets of the enzymes, to understand how G9a and GLP influence biological responses beyond their effect on histone proteins. Emphasis will be placed on highlighting the latest discoveries and examining the experimental details of several key studies that have contributed to our current understanding of the biological significance of G9a and GLP.

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References

  • Abu-Zhayia ER, Awwad SW, Ben-Oz BM et al (2018) CDYL1 fosters double-strand break-induced transcription silencing and promotes homology-directed repair. J Mol Cell Biol 10:341–357

    Article  CAS  PubMed  Google Scholar 

  • Allis CD, Berger SL, Cote J et al (2007) New nomenclature for chromatin-modifying enzymes. Cell 131:633–636

    Article  CAS  PubMed  Google Scholar 

  • Alves-Silva JC, de Carvalho JL, Rabello DA et al (2018) GLP overexpression is associated with poor prognosis in chronic lymphocytic leukemia and its inhibition induces leukemic cell death. Investig New Drugs 36:955–960

    Article  CAS  Google Scholar 

  • Anderson AM, Kalimutho M, Harten S et al (2017) The metastasis suppressor RARRES3 as an endogenous inhibitor of the immunoproteasome expression in breast cancer cells. Sci Rep 7:39873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Antignano F, Burrows K, Hughes MR et al (2014) Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation. J Clin Invest 124:1945–1955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balemans MC, Huibers MM, Eikelenboom NW et al (2010) Reduced exploration, increased anxiety, and altered social behavior: autistic-like features of euchromatin histone methyltransferase 1 heterozygous knockout mice. Behav Brain Res 208:47–55

    Article  CAS  PubMed  Google Scholar 

  • Balemans MC, Ansar M, Oudakker AR et al (2014) Reduced euchromatin histone methyltransferase 1 causes developmental delay, hypotonia, and cranial abnormalities associated with increased bone gene expression in Kleefstra syndrome mice. Dev Biol 386:395–407

    Article  CAS  PubMed  Google Scholar 

  • Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21:381–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Battisti V, Pontis J, Boyarchuk E et al (2016) Unexpected distinct roles of the related histone H3 lysine 9 methyltransferases G9a and G9a-like protein in myoblasts. J Mol Biol 428:2329–2343

    Article  CAS  PubMed  Google Scholar 

  • Benevento M, van de Molengraft M, van Westen R et al (2015) The role of chromatin repressive marks in cognition and disease: a focus on the repressive complex GLP/G9a. Neurobiol Learn Mem 124:88–96

    Article  CAS  PubMed  Google Scholar 

  • Benevento M, Oomen CA, Horner AE et al (2017) Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation. Sci Rep 7:40284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bian C, Chen Q, Yu X (2015) The zinc finger proteins ZNF644 and WIZ regulate the G9a/GLP complex for gene repression. elife 4

    Google Scholar 

  • Bittencourt D, Wu DY, Jeong KW et al (2012) G9a functions as a molecular scaffold for assembly of transcriptional coactivators on a subset of glucocorticoid receptor target genes. Proc Natl Acad Sci U S A 109:19673–19678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blackburn PR, Tischer A, Zimmermann MT et al (2017) A novel Kleefstra syndrome-associated variant that affects the conserved TPLX motif within the ankyrin repeat of EHMT1 leads to abnormal protein folding. J Biol Chem 292:3866–3876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bock I, Németh K, Pentelényi K et al (2016) Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance. Gene 595:131–141

    Article  CAS  PubMed  Google Scholar 

  • Bretones G, Delgado MD, León J (2015) Myc and cell cycle control. Biochim Biophys Acta 1849:506–516

    Article  CAS  PubMed  Google Scholar 

  • Brown SE, Campbell RD, Sanderson CM (2001) Novel NG36/G9a gene products encoded within the human and mouse MHC class III regions. Mamm Genome 12:916–924

    Article  CAS  PubMed  Google Scholar 

  • Casciello F, Windloch K, Gannon F et al (2015) Functional role of G9a histone methyltransferase in cancer. Front Immunol 6:487

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Casciello F, Al-Ejeh F, Kelly G et al (2017) G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis. Proc Natl Acad Sci U S A 114:7077–7082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaib H, Nebbioso A, Prebet T et al (2012) Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1. Leukemia 26:662–674

    Article  CAS  PubMed  Google Scholar 

  • Chang Y, Zhang X, Horton JR et al (2009) Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol 16:312–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaturvedi CP, Brand M (2014) EHMT2 (euchromatic histone-lysine N-methyltransferase 2). Atlas Genet Cytogenet Oncol Haematol 18:38–45

    Google Scholar 

  • Chaturvedi CP, Hosey AM, Palii C et al (2009) 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 106(43):18303–18308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaturvedi CP, Somasundaram B, Singh K et al (2012) Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A. Proc Natl Acad Sci U S A 109:18845–18850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen MW, Hua KT, Kao HJ et al (2010) H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res 70:7830–7840

    Article  CAS  PubMed  Google Scholar 

  • Cheung HC, Yatsenko SA, Kadapakkam M et al (2012) Constitutional tandem duplication of 9q34 that truncates EHMT1 in a child with ganglioglioma. Pediatr Blood Cancer 58:801–805

    Article  PubMed  Google Scholar 

  • Chin HG, Estève PO, Pradhan M et al (2007) Automethylation of G9a and its implication in wider substrate specificity and HP1 binding. Nucleic Acids Res 35:7313–7323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho HS, Kelly JD, Hayami S et al (2011) Enhanced expression of EHMT2 is involved in the proliferation of cancer cells through negative regulation of SIAH1. Neoplasia 13:676–684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi JY, Yoon SS, Kim SE et al (2017) KDM4B histone demethylase and G9a regulate expression of vascular adhesion proteins in cerebral microvessels. Sci Rep 7:45005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collins R, Cheng X (2010) A case study in cross-talk: the histone lysine methyltransferases G9a and GLP. Nucleic Acids Res 38:3503–3511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collins RE, Northrop JP, Horton JR et al (2008) The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and dimethyllysine binding modules. Nat Struct Mol Biol 15:245–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curry E, Green I, Chapman-Rothe N et al (2015) Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells. Clin Epigenetics 7:84

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dai W, Kloner RA (2011) Bone marrow-derived cell transplantation therapy for myocardial infarction: lessons learned and future questions. Am J Transplant 11:2297–2301

    Article  CAS  PubMed  Google Scholar 

  • Davis BA, David F, O’Regan C et al (2018) Ehmt1 forebrain haploinsufficiency leads to impaired memory, sensory gating and information processing. bioRxiv:257626

    Google Scholar 

  • Dillon SC, Zhang X, Trievel RC et al (2005) The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol 6:227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ding J, Li T, Wang X et al (2013) The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation. Cell Metab 18:896–907

    Article  CAS  PubMed  Google Scholar 

  • Duffy MJ, Synnott NC, McGowan PM et al (2014) p53 as a target for the treatment of cancer. Cancer Treat Rev 40:1153–1160

    Article  CAS  PubMed  Google Scholar 

  • Dunham I, Sargent CA, Kendall E et al (1990) Characterization of the class III region in different MHC haplotypes by pulsed-field gel electrophoresis. Immunogenetics 32:175–182

    Article  CAS  PubMed  Google Scholar 

  • Estève PO, Patnaik D, Chin HG et al (2005) Functional analysis of the N- and C-terminus of mammalian G9a histone H3 methyltransferase. Nucleic Acids Res 33:3211–3223

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Estève PO, Chin HG, Smallwood A et al (2006) Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev 20:3089–3103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Feldman N, Gerson A, Fang J et al (2006) G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat Cell Biol 8:188–194

    Article  CAS  PubMed  Google Scholar 

  • Ferguson D, Koo JW, Feng J et al (2013) Essential role of SIRT1 signaling in the nucleus accumbens in cocaine and morphine action. J Neurosci 33:16088–16098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fiszbein A, Giono LE, Quaglino A et al (2016) Alternative splicing of G9a regulates neuronal differentiation. Cell Rep 14:2797–2808

    Article  CAS  PubMed  Google Scholar 

  • Fritsch L, Robin P, Mathieu JR et al (2010) A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex. Mol Cell 37:46–56

    Article  CAS  PubMed  Google Scholar 

  • Gupta-Agarwal S, Franklin AV, Deramus T et al (2012) G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. J Neurosci 32:5440–5453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harada N, Visser R, Dawson A et al (2004) A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome. J Hum Genet 49:440–444

    Article  CAS  PubMed  Google Scholar 

  • He X, Caluseriu O, Srivastava R et al (2016) Reversible white matter lesions associated with mutant EHMT1 and Kleefstra syndrome. Neurol Genet 2:e58

    Article  PubMed  PubMed Central  Google Scholar 

  • Herreros-Villanueva M, Zhang JS, Koenig A et al (2013) SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells. Oncogene 2:e61

    Article  CAS  Google Scholar 

  • Hu L, Zang MD, Wang HX et al (2018) G9A promotes gastric cancer metastasis by upregulating ITGB3 in a SET domain-independent manner. Cell Death Dis 9:278

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hua KT, Wang MY, Chen MW et al (2014) The H3K9 methyltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis. Mol Cancer 13:189

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Huang C, Xiang Y, Wang Y et al (2010a) Dual-specificity histone demethylase KIAA1718 (KDM7A) regulates neural differentiation through FGF4. Cell Res 20:154–165

    Article  CAS  PubMed  Google Scholar 

  • Huang J, Dorsey J, Chuikov S et al (2010b) G9a and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem 285:9636–9641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang T, Zhang P, Li W et al (2017) G9A promotes tumor cell growth and invasion by silencing CASP1 in non-small-cell lung cancer cells. Cell Death Dis 8:e2726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huber R, Pietsch D, Panterodt T et al (2012) Regulation of C/EBPβ and resulting functions in cells of the monocytic lineage. Cell Signal 24:1287–1296

    Article  CAS  PubMed  Google Scholar 

  • Inagaki T, Sakai J, Kajimura S (2016) Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat Rev Mol Cell Biol 17:480–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inagawa M, Nakajima K, Makino T et al (2013) Histone H3 lysine 9 methyltransferases, G9a and GLP are essential for cardiac morphogenesis. Mech Dev 130:519–531

    Article  CAS  PubMed  Google Scholar 

  • Isham CR, Tibodeau JD, Jin W et al (2007) Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress. Blood 109:2579–2588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwasa E, Hamashima Y, Fujishiro S et al (2010) Total synthesis of (+)-chaetocin and its analogues: their histone methyltransferase G9a inhibitory activity. J Am Chem Soc 132:4078–4079

    Article  CAS  PubMed  Google Scholar 

  • Iwase S, Bérubé NG, Zhou Z et al (2017) Epigenetic etiology of intellectual disability. J Neurosci 37:10773–10782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang R, Hua C, Wan Y et al (2015) Hephaestin and ceruloplasmin play distinct but interrelated roles in iron homeostasis in mouse brain. J Nutr 145:1003–1009

    Article  CAS  PubMed  Google Scholar 

  • Karpova NN, Sales AJ, Joca SR (2017) Epigenetic basis of neuronal and synaptic plasticity. Curr Top Med Chem 17:771–793

    Article  CAS  PubMed  Google Scholar 

  • Katoh K, Yamazaki R, Onishi A et al (2012) G9a histone methyltransferase activity in retinal progenitors is essential for proper differentiation and survival of mouse retinal cells. J Neurosci 32:17658–17670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaur K, Yang J, Edwards JG et al (2016) G9a histone methyltransferase inhibitor BIX01294 promotes expansion of adult cardiac progenitor cells without changing their phenotype or differentiation potential. Cell Prolif 49:373–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ke XX, Zhang D, Zhu S et al (2014) Inhibition of H3K9 methyltransferase G9a repressed cell proliferation and induced autophagy in neuroblastoma cells. PLoS One 9:e106962

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim H, Choi JD, Kim BG et al (2016a) Interactome analysis reveals that heterochromatin protein 1γ (HP1γ) Is associated with the DNA damage response pathway. Cancer Res Treat 48:322–333

    Article  CAS  PubMed  Google Scholar 

  • Kim SY, Morales CR, Gillette TG et al (2016b) Epigenetic regulation in heart failure. Curr Opin Cardiol 31:255–265

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim K, Son MY, Jung CR et al (2018) EHMT2 is a metastasis regulator in breast cancer. Biochem Biophys Res Commun 496:758–762

    Article  CAS  PubMed  Google Scholar 

  • Kleefstra T, Brunner HG, Amiel J et al (2006) Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am J Hum Genet 79:370–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kleefstra T, van Zelst-Stams WA, Nillesen WM et al (2009) Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet 46:598–606

    Article  CAS  PubMed  Google Scholar 

  • Kondengaden SM, Luo LF, Huang K et al (2016) Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines. Eur J Med Chem 122:382–393

    Article  CAS  PubMed  Google Scholar 

  • Kowolik CM, Lin M, Xie J et al (2016) NT1721, a novel epidithiodiketopiperazine, exhibits potent in vitro and in vivo efficacy against acute myeloid leukemia. Oncotarget 7:86186–86197

    Article  PubMed  PubMed Central  Google Scholar 

  • Kramer JM (2016) Regulation of cell differentiation and function by the euchromatin histone methyltranserfases G9a and GLP. Biochem Cell Biol 94:26–32

    Article  CAS  PubMed  Google Scholar 

  • Krivega I, Byrnes C, de Vasconcellos JF et al (2015) Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping. Blood 126:665–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kubicek S, O’Sullivan RJ, August EM et al (2007) Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell 25:473–481

    Article  CAS  PubMed  Google Scholar 

  • Lee DY, Northrop JP, Kuo MH et al (2006) Histone H3 lysine 9 methyltransferase G9a is a transcriptional coactivator for nuclear receptors. J Biol Chem 281:8476–8485

    Article  CAS  PubMed  Google Scholar 

  • Lee SH, Kim J, Kim WH et al (2009) Hypoxic silencing of tumor suppressor RUNX3 by histone modification in gastric cancer cells. Oncogene 28:184–194

    Article  CAS  PubMed  Google Scholar 

  • Lee JS, Kim Y, Kim IS et al (2010) Negative regulation of hypoxic responses via induced Reptin methylation. Mol Cell 39:71–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JS, Kim Y, Bhin J et al (2011) Hypoxia-induced methylation of a pontin chromatin remodeling factor. Proc Natl Acad Sci U S A 108:13510–13515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lehnertz B, Northrop JP, Antignano F et al (2010) Activating and inhibitory functions for the histone lysine methyltransferase G9a in T helper cell differentiation and function. J Exp Med 207:915–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lehnertz B, Pabst C, Su L et al (2014) The methyltransferase G9a regulates HoxA9-dependent transcription in AML. Genes Dev 28:317–327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lenstra DC, Al Temimi AHK, Mecinović J (2018) Inhibition of histone lysine methyltransferases G9a and GLP by ejection of structural Zn(II). Bioorg Med Chem Lett 28(7):1234–1238

    Article  CAS  PubMed  Google Scholar 

  • Ling BM, Bharathy N, Chung TK et al (2012) Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation. Proc Natl Acad Sci U S A 109:841–846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu F, Chen X, Allali-Hassani A et al (2009) Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a. J Med Chem 52:7950–7953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu F, Chen X, Allali-Hassani A et al (2010) Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines. J Med Chem 53:5844–5857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu F, Barsyte-Lovejoy D, Allali-Hassani A et al (2011) Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy-quinazolines. J Med Chem 54:6139–6150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu F, Barsyte-Lovejoy D, Li F et al (2013) Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J Med Chem 56:8931–8942

    Article  CAS  PubMed  Google Scholar 

  • Liu N, Zhang Z, Wu H et al (2015a) Recognition of H3K9 methylation by GLP is required for efficient establishment of H3K9 methylation, rapid target gene repression, and mouse viability. Genes Dev 29:379–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, Ye D, Guo W et al (2015b) G9a is essential for EMT-mediated metastasis and maintenance of cancer stem cell-like characters in head and neck squamous cell carcinoma. Oncotarget 6:6887–6901

    PubMed  PubMed Central  Google Scholar 

  • Lu Z, Tian Y, Salwen HR et al (2013) Histone-lysine methyltransferase EHMT2 is involved in proliferation, apoptosis, cell invasion, and DNA methylation of human neuroblastoma cells. Anti-Cancer Drugs 24:484–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinez SR, Gay MS, Zhang L (2015) Epigenetic mechanisms in heart development and disease. Drug Discov Today 20:799–811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayr C, Helm K, Jakab M et al (2018) The histone methyltransferase G9a: a new therapeutic target in biliary tract cancer. Hum Pathol 72:117–126

    Article  CAS  PubMed  Google Scholar 

  • Maze I, Covington HE, Dietz DM et al (2010) Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 327:213–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mezentseva NV, Yang J, Kaur K et al (2013) The histone methyltransferase inhibitor BIX01294 enhances the cardiac potential of bone marrow cells. Stem Cells Dev 22:654–667

    Article  CAS  PubMed  Google Scholar 

  • Milner CM, Campbell RD (1993) The G9a gene in the human major histocompatibility complex encodes a novel protein containing ankyrin-like repeats. Biochem J 290:811–818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore KE, Carlson SM, Camp ND et al (2013) A general molecular affinity strategy for global detection and proteomic analysis of lysine methylation. Mol Cell 50:444–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morales M, Arenas EJ, Urosevic J et al (2014) RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation. EMBO Mol Med 6:865–881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mozzetta C, Pontis J, Fritsch L et al (2014) The histone H3 lysine 9 methyltransferases G9a and GLP regulate polycomb repressive complex 2-mediated gene silencing. Mol Cell 53:277–289

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi T, Markwald RR, Baldwin HS et al (2016) Etiology and morphogenesis of congenital heart disease: from gene function and cellular interaction to morphology. Springer, Tokyo

    Book  Google Scholar 

  • Oh ST, Kim KB, Chae YC et al (2014) H3K9 histone methyltransferase G9a-mediated transcriptional activation of p21. FEBS Lett 588:685–691

    Article  CAS  PubMed  Google Scholar 

  • Ohno H, Shinoda K, Ohyama K et al (2013) EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504:163–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okur V, Nees S, Chung WK et al (2018) Pulmonary hypertension in patients with 9q34.3 microdeletion-associated Kleefstra syndrome. Am J Med Genet A 176:1773–1777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oliveira F, Rocha S, Fernandes R (2014) Iron metabolism: from health to disease. J Clin Lab Anal 28:210–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olsen JB, Wong L, Deimling S et al (2016) G9a and ZNF644 physically associate to suppress progenitor gene expression during neurogenesis. Stem Cell Reports 7:454–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pappano WN, Guo J, He Y et al (2015) The histone methyltransferase inhibitor A-366 uncovers a role for G9a/GLP in the epigenetics of leukemia. PLoS One 10:e0131716

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pless O, Kowenz-Leutz E, Knoblich M et al (2008) G9a-mediated lysine methylation alters the function of CCAAT/enhancer-binding protein-beta. J Biol Chem 283:26357–26363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Poulard C, Bittencourt D, Wu DY et al (2017) A post-translational modification switch controls coactivator function of histone methyltransferases G9a and GLP. EMBO Rep 18:1442–1459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Purcell DJ, Jeong KW, Bittencourt D et al (2011) A distinct mechanism for coactivator versus corepressor function by histone methyltransferase G9a in transcriptional regulation. J Biol Chem 286:41963–41971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rathert P, Dhayalan A, Murakami M et al (2008) Protein lysine methyltransferase G9a acts on non-histone targets. Nat Chem Biol 4:344–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raza M, Chakraborty S, Choudhury M et al (2014) Cellular iron homeostasis and therapeutic implications of iron chelators in cancer. Curr Pharm Biotechnol 15:1125–1140

    Article  CAS  PubMed  Google Scholar 

  • Rump A, Hildebrand L, Tzschach A et al (2013) A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring. Eur J Hum Genet 21:887–890

    Article  CAS  PubMed  Google Scholar 

  • Sahara S, Aoto M, Eguchi Y et al (1999) Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation. Nature 401:168–173

    Article  CAS  PubMed  Google Scholar 

  • Sampath SC, Marazzi I, Yap KL et al (2007) Methylation of a histone mimic within the histone methyltransferase G9a regulates protein complex assembly. Mol Cell 27:596–608

    Article  CAS  PubMed  Google Scholar 

  • Scheer S, Zaph C (2017) The lysine methyltransferase G9a in immune cell differentiation and function. Front Immunol 8:429

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schotta G, Ebert A, Krauss V et al (2002) Central role of Drosophila SU(VAR)3-9 in histone H3-K9 methylation and heterochromatic gene silencing. EMBO J 21:1121–1131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shankar SR, Bahirvani AG, Rao VK et al (2013) G9a, a multipotent regulator of gene expression. Epigenetics 8:16–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi Y, Desponts C, Do JT et al (2008a) Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3:568–574

    Article  CAS  PubMed  Google Scholar 

  • Shi Y, Do JT, Desponts C et al (2008b) A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2:525–528

    Article  CAS  PubMed  Google Scholar 

  • Shinkai Y, Tachibana M (2011) H3K9 methyltransferase G9a and the related molecule GLP. Genes Dev 25:781–788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smallwood A, Estève PO, Pradhan S et al (2007) Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev 21:1169–1178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spies T, Bresnahan M, Strominger JL (1989) Human major histocompatibility complex contains a minimum of 19 genes between the complement cluster and HLA-B. Proc Natl Acad Sci U S A 86:8955–8958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spinella JF, Cassart P, Richer C et al (2016) Genomic characterization of pediatric T-cell acute lymphoblastic leukemia reveals novel recurrent driver mutations. Oncotarget 7:65485–65503

    Article  PubMed  PubMed Central  Google Scholar 

  • Suganuma T, Workman JL (2011) Signals and combinatorial functions of histone modifications. Annu Rev Biochem 80:473–499

    Article  CAS  PubMed  Google Scholar 

  • Sweis RF, Pliushchev M, Brown PJ et al (2014) Discovery and development of potent and selective inhibitors of histone methyltransferase G9a. ACS Med Chem Lett 5:205–209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tachibana M, Sugimoto K, Fukushima T et al (2001) Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J Biol Chem 276:25309–25317

    Article  CAS  PubMed  Google Scholar 

  • Tachibana M, Sugimoto K, Nozaki M et al (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16:1779–1791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tachibana M, Ueda J, Fukuda M et al (2005) Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev 19:815–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    Article  CAS  PubMed  Google Scholar 

  • Thienpont B, Aronsen JM, Robinson EL et al (2017) The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy. J Clin Invest 127:335–348

    Article  PubMed  Google Scholar 

  • Torti SV, Torti FM (2013) Iron and cancer: more ore to be mined. Nat Rev Cancer 13:342–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uhlen M, Bandrowski A, Carr S et al (2016) A proposal for validation of antibodies. Nat Methods 13:823–827

    Article  CAS  PubMed  Google Scholar 

  • Upadhyay AK, Cheng X (2011) Dynamics of histone lysine methylation: structures of methyl writers and erasers. Prog Drug Res 67:107–124

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vargiami E, Ververi A, Al-Mutawa H et al (2016) Multiple coronary artery microfistulas in a girl with Kleefstra syndrome. Case Rep Genet 2016:3056053

    PubMed  PubMed Central  Google Scholar 

  • Vedadi M, Barsyte-Lovejoy D, Liu F et al (2011) A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol 7:566–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Venkatesh S, Workman JL (2015) Histone exchange, chromatin structure and the regulation of transcription. Nat Rev Mol Cell Biol 16:178–189

    Article  CAS  PubMed  Google Scholar 

  • Verbaro DJ, Sakurai N, Kim B et al (2018) Cutting edge: the histone methyltransferase G9a Is required for silencing of helper T lineage-associated genes in proliferating CD8 T cells. J Immunol 200:3891–3896

    Article  CAS  PubMed  Google Scholar 

  • Vieler M, Sanyal S (2018) p53 isoforms and their implications in cancer. Cancers (Basel) 10(9):288

    Article  Google Scholar 

  • Wada S, Ideno H, Shimada A et al (2015) H3K9MTase G9a is essential for the differentiation and growth of tenocytes in vitro. Histochem Cell Biol 144:13–20

    Article  CAS  PubMed  Google Scholar 

  • Wan YCE, Liu J, Chan KM (2018) Histone H3 mutations in cancer. Curr Pharmacol Rep 4:292–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Z, Zang C, Rosenfeld JA et al (2008) Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet 40:897–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Qin J, Wang S et al (2016) Conversion of human gastric epithelial cells to multipotent endodermal progenitors using defined small molecules. Cell Stem Cell 19:449–461

    Article  CAS  PubMed  Google Scholar 

  • Wang YF, Zhang J, Su Y et al (2017) G9a regulates breast cancer growth by modulating iron homeostasis through the repression of ferroxidase hephaestin. Nat Commun 8:274

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wei L, Chiu DK, Tsang FH et al (2017) Histone methyltransferase G9a promotes liver cancer development by epigenetic silencing of tumor suppressor gene RARRES3. J Hepatol 67:758–769

    Article  CAS  PubMed  Google Scholar 

  • Willemsen MH, Beunders G, Callaghan M et al (2011) Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions. Clin Genet 80:31–38

    Article  CAS  PubMed  Google Scholar 

  • Willemsen MH, Vulto-van Silfhout AT, Nillesen WM et al (2012) Update on Kleefstra syndrome. Mol Syndromol 2:202–212

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu G, Fang Y, Lu ZH et al (1998) Induction of axon-like and dendrite-like processes in neuroblastoma cells. J Neurocytol 27:1–14

    Article  CAS  PubMed  Google Scholar 

  • Wu H, Chen X, Xiong J et al (2011) Histone methyltransferase G9a contributes to H3K27 methylation in vivo. Cell Res 21:365–367

    Article  CAS  PubMed  Google Scholar 

  • Wysoczynski M, Hong KU, Moore JB (2014) Bone marrow cell therapies in ischemic cardiomyopathy. Expert Opin Biol Ther 14:1229–1232

    Article  PubMed  Google Scholar 

  • Xiong Y, Li F, Babault N et al (2017a) Discovery of potent and selective inhibitors for G9a-like protein (GLP) lysine methyltransferase. J Med Chem 60:1876–1891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong Y, Li F, Babault N et al (2017b) Structure-activity relationship studies of G9a-like protein (GLP) inhibitors. Bioorg Med Chem 25:4414–4423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamada A, Shimura C, Shinkai Y (2018) Biochemical validation of EHMT1 missense mutations in Kleefstra syndrome. J Hum Genet 63:555–562

    Article  CAS  PubMed  Google Scholar 

  • Yang J, Kaur K, Ong LL et al (2015) Inhibition of G9a histone methyltransferase converts bone marrow mesenchymal stem cells to cardiac competent progenitors. Stem Cells Int 2015:270428

    PubMed  PubMed Central  Google Scholar 

  • Yang J, Kaur K, Edwards JG et al (2017) Inhibition of histone methyltransferase, histone deacetylase, and β-catenin synergistically enhance the cardiac potential of bone marrow cells. Stem Cells Int 2017:3464953

    PubMed  PubMed Central  Google Scholar 

  • Yang Y, Shen J, Yan D et al (2018) Euchromatic histone lysine methyltransferase 1 regulates cancer development in human gastric cancer by regulating E-cadherin. Oncol Lett 15:9480–9486

    PubMed  PubMed Central  Google Scholar 

  • Yuan Y, Wang Q, Paulk J et al (2012) A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chem Biol 7:1152–1157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zentner GE, Henikoff S (2013) Regulation of nucleosome dynamics by histone modifications. Nat Struct Mol Biol 20:259–266

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Huang Y, Shi X (2015) Emerging roles of lysine methylation on non-histone proteins. Cell Mol Life Sci 72:4257–4272

    Article  CAS  PubMed  Google Scholar 

  • Zhang RH, Judson RN, Liu DY et al (2016a) The lysine methyltransferase Ehmt2/G9a is dispensable for skeletal muscle development and regeneration. Skelet Muscle 6:22

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang X, Peng D, Xi Y et al (2016b) G9a-mediated methylation of ERα links the PHF20/MOF histone acetyltransferase complex to hormonal gene expression. Nat Commun 7:10810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Wang Y, Shen Y et al (2018) G9a stimulates CRC growth by inducing p53 Lys373 dimethylation-dependent activation of Plk1. Theranostics 8:2884–2895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhong X, Chen X, Guan X et al (2015) Overexpression of G9a and MCM7 in oesophageal squamous cell carcinoma is associated with poor prognosis. Histopathology 66:192–200

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Departments of Physiology and Medicine, New York Medical College, Valhalla, NY, USA

    Carol A. Eisenberg & Leonard M. Eisenberg

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  1. Carol A. Eisenberg
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  2. Leonard M. Eisenberg
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  1. Nanobiomedical Center, Adam Mickiewicz University, Poznań, Poland

    Stefan Jurga

  2. Nanobiomedical Center, Adam Mickiewicz University, Poznań, Poland

    Jan Barciszewski

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Eisenberg, C.A., Eisenberg, L.M. (2019). G9a and G9a-Like Histone Methyltransferases and Their Effect on Cell Phenotype, Embryonic Development, and Human Disease. In: Jurga, S., Barciszewski, J. (eds) The DNA, RNA, and Histone Methylomes. RNA Technologies. Springer, Cham. https://doi.org/10.1007/978-3-030-14792-1_16

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