Skip to main content

Advertisement

SpringerLink
Log in

Histone methyltransferases: regulation of transcription and contribution to human disease

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Histone modifications contribute to the precise regulation of transcription by recruiting non-histone proteins and controlling chromatin conformation. These covalent modifications are dynamically regulated by many enzymes that modify histones at specific residues in different ways. Histone modifiers contribute to development as well as cellular responses to extracellular stimuli. Mutations in the genes encoding them cause various diseases, including developmental disorders and certain malignancies. Haploinsufficiency for some histone methyltransferases, one of the principal modifiers of the histone modification network, are associated with particular congenital diseases, including Sotos syndrome, Wolf–Hirschhorn syndrome, and 9q syndrome. In this review, we discuss the molecular function of the histone methyltransferases and the human diseases associated with their dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705

    Article  CAS  PubMed  Google Scholar 

  2. Baker LA, Allis CD, Wang GG (2008) PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks. Mutat Res, Fundam Mol Mech Mutagen 647:3–12

    Article  CAS  Google Scholar 

  3. Klose RJ, Zhang Y (2007) Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol 8:307–318

    Article  CAS  PubMed  Google Scholar 

  4. Sims RJ, Reinberg D (2006) Histone H3 Lys 4 methylation: caught in a bind? Genes Dev 20:2779–2786

    Article  CAS  PubMed  Google Scholar 

  5. Maurer-Stroh S, Dickens NJ, Hughes-Davies L et al (2003) The tudor domain ‘royal family’: tudor, plant agenet, chromo, PWWP and MBT domains. Trends Biochem Sci 28:69–74

    Article  CAS  PubMed  Google Scholar 

  6. Bhaumik SR, Smith E, Shilatifard A (2007) Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol 14:1008–1016

    Article  CAS  PubMed  Google Scholar 

  7. Barski A, Cuddapah S, Cui K et al (2007) High-resolution profiling of histone methylations in the human genome. Cell 129:823–837

    Article  CAS  PubMed  Google Scholar 

  8. Mikkelsen TS, Ku M, Jaffe DB et al (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448:553–560

    Article  CAS  PubMed  Google Scholar 

  9. Heintzman ND, Stuart RK, Hon G et al (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39:311–318

    Article  CAS  PubMed  Google Scholar 

  10. Wang P, Lin C, Smith ER et al (2009) Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol Cell Biol 29:6074–6085

    Article  CAS  PubMed  Google Scholar 

  11. Milne TA, Briggs SD, Brock HW et al (2002) MLL targets set domain methyltransferase activity to hox gene promoters. Mol Cell 10:1107–1117

    Article  CAS  PubMed  Google Scholar 

  12. Steward MM, Lee J, O’Donovan A et al (2006) Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nat Struct Mol Biol 13:852–854

    Article  CAS  PubMed  Google Scholar 

  13. Wysocka J, Myers MP, Laherty CD et al (2003) Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev 17:896–911

    Article  CAS  PubMed  Google Scholar 

  14. Gregory GD, Vakoc CR, Rozovskaia T et al (2007) Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes. Mol Cell Biol 27:8466–8479

    Article  CAS  PubMed  Google Scholar 

  15. Hamamoto R, Furukawa Y, Morita M et al (2004) SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol 6:731–740

    Article  CAS  PubMed  Google Scholar 

  16. Chuikov S, Kurash JK, Wilson JR et al (2004) Regulation of p53 activity through lysine methylation. Nature 432:353–360

    Article  CAS  PubMed  Google Scholar 

  17. Tan X, Rotllant J, Li H et al (2006) SmyD1, a histone methyltransferase, is required for myofibril organization and muscle contraction in zebrafish embryos. Proc Natl Acad Sci USA 103:2713–2718

    Article  CAS  PubMed  Google Scholar 

  18. Gottlieb PD, Pierce SA, Sims RJ et al (2002) Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis. Nat Genet 31:25–32

    CAS  PubMed  Google Scholar 

  19. Vermeulen M, Mulder KW, Denissov S et al (2007) Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 Lysine 4. Cell 131:58–69

    Article  CAS  PubMed  Google Scholar 

  20. Shi X, Hong T, Walter KL et al (2006) ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442:96–99

    Article  CAS  PubMed  Google Scholar 

  21. Peña PV, Davrazou F, Shi X et al (2006) Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 442:100–103

    PubMed  Google Scholar 

  22. Kim K, Geng L, Huang S (2003) Inactivation of a histone methyltransferase by mutations in human cancers. Cancer Res 63:7619–7623

    CAS  PubMed  Google Scholar 

  23. Matsui T, Leung D, Miyashita H et al (2010) Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464:927–931

    Article  CAS  PubMed  Google Scholar 

  24. Kim J, Daniel J, Espejo A et al (2006) Tudor, MBT and chromo domains gauge the degree of lysine methylation. EMBO Rep 7:397–430

    CAS  PubMed  Google Scholar 

  25. Karagianni P, Amazit L, Qin J et al (2008) ICBP90, a novel methyl K9 H3 binding protein linking protein ubiquitination with heterochromatin formation. Mol Cell Biol 28:705–717

    Article  CAS  PubMed  Google Scholar 

  26. Iwase S, Lan F, Bayliss P et al (2007) The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 128:1077–1088

    Article  CAS  PubMed  Google Scholar 

  27. Jensen L, Amende M, Gurok U et al (2005) Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Am J Hum Genet 76:227–236

    Article  CAS  PubMed  Google Scholar 

  28. Cao R, Wang L, Wang H et al (2002) Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science 298:1039–1043

    Article  CAS  PubMed  Google Scholar 

  29. Fiskus W, Wang Y, Sreekumar A et al (2009) Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 114:2733–2743

    CAS  PubMed  Google Scholar 

  30. Simon JA, Lange CA (2008) Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res, Fundam Mol Mech Mutagen 647:21–29

    Article  CAS  Google Scholar 

  31. Tan J, Yang X, Zhuang L et al (2007) Pharmacologic disruption of polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 21:1050–1063

    Article  CAS  PubMed  Google Scholar 

  32. Miranda TB, Cortez CC, Yoo CB et al (2009) DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther 8:1579–1588

    Article  CAS  PubMed  Google Scholar 

  33. Rayasam GV, Wendling O, Angrand PO et al (2003) NSD1 is essential for early post-implantation development and has a catalytically active SET domain. EMBO J 22:3153–3163

    Article  CAS  PubMed  Google Scholar 

  34. Nimura K, Ura K, Shiratori H et al (2009) A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf–Hirschhorn syndrome. Nature 460:287–291

    Article  CAS  PubMed  Google Scholar 

  35. Brown MA, Sims RJ, Gottlieb PD et al (2006) Identification and characterization of Smyd 2: a split SET/MYND domain-containing histone H 3 lysine 36-specific methyltransferase that interacts with the Sin 3 histone deacetylase complex. Mol Cancer 5:26

    Article  PubMed  Google Scholar 

  36. Edmunds JW, Mahadevan LC, Clayton AL (2007) Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J 27:406–420

    Article  PubMed  Google Scholar 

  37. Sun X, Wei J, Wu X et al (2005) Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase. J Biol Chem 280:35261–35271

    Article  CAS  PubMed  Google Scholar 

  38. Luco RF, Pan Q, Tominaga K et al (2010) Regulation of alternative splicing by histone modifications. Science 327:996–1000

    Article  CAS  PubMed  Google Scholar 

  39. Zhang P, Du J, Sun B et al (2006) Structure of human MRG 15 chromo domain and its binding to Lys 36-methylated histone H 3. Nucleic Acids Res 34:6621–6628

    Article  CAS  PubMed  Google Scholar 

  40. Carrozza MJ, Li B, Florens L et al (2005) Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 123:581–592

    Article  CAS  PubMed  Google Scholar 

  41. Keogh MC, Kurdistani SK, Morris SA et al (2005) Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell 123:593–605

    Article  CAS  PubMed  Google Scholar 

  42. Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6:838–849

    Article  CAS  PubMed  Google Scholar 

  43. Botuyan MV, Lee J, Ward IM et al (2006) Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 127:1361–1373

    Article  CAS  PubMed  Google Scholar 

  44. Huyen Y, Zgheib O, DiTullio RA Jr et al (2004) Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432:406–411

    Article  CAS  PubMed  Google Scholar 

  45. Okada Y, Feng Q, Lin Y et al (2005) hDOT1L links histone methylation to leukemogenesis. Cell 121:167–178

    Article  CAS  PubMed  Google Scholar 

  46. Jones B, Su H, Bhat A et al (2008) The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure. PLoS Genet 4:e1000190

    Article  PubMed  Google Scholar 

  47. Nishioka K, Rice JC, Sarma K et al (2002) PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol Cell 9:1201–1213

    Article  CAS  PubMed  Google Scholar 

  48. Schotta G, Lachner M, Sarma K et al (2004) A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev 18:1251–1262

    Article  CAS  PubMed  Google Scholar 

  49. Marango J, Shimoyama M, Nishio H et al (2008) The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood 111:3145–3154

    Article  CAS  PubMed  Google Scholar 

  50. Oda H, Okamoto I, Murphy N et al (2009) Monomethylation of histone H4-lysine 20 is involved in chromosome structure and stability and is essential for mouse development. Mol Cell Biol 29:2278–2295

    Article  CAS  PubMed  Google Scholar 

  51. Trojer P, Li G, Sims RJ III et al (2007) L3MBTL1, a histone-methylation-dependent chromatin lock. Cell 129:915–928

    Article  CAS  PubMed  Google Scholar 

  52. Krause CD, Yang Z, Kim Y et al (2007) Protein arginine methyltransferases: evolution and assessment of their pharmacological and therapeutic potential. Pharmacol Ther 113:50–87

    Article  CAS  PubMed  Google Scholar 

  53. Bedford MT, Richard S (2005) Arginine methylation: an emerging regulator of protein function. Mol Cell 18:263–272

    Article  CAS  PubMed  Google Scholar 

  54. Kirmizis A, Santos-Rosa H, Penkett CJ et al (2009) Distinct transcriptional outputs associated with mono- and dimethylated histone H3 arginine 2. Nat Struct Mol Biol 16:449–451

    Article  CAS  PubMed  Google Scholar 

  55. Guccione E, Bassi C, Casadio F et al (2007) Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature 449:933–937

    Article  CAS  PubMed  Google Scholar 

  56. Hyllus D, Stein C, Schnabel K et al (2007) PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation. Genes Dev 21:3369–3380

    Article  CAS  PubMed  Google Scholar 

  57. Iberg AN, Espejo A, Cheng D et al (2008) Arginine methylation of the histone H3 tail impedes effector binding. J Biol Chem 283:3006–3010

    Article  CAS  PubMed  Google Scholar 

  58. Li B, Carey M, Workman J (2007) The role of chromatin during transcription. Cell 128:707–719

    Article  CAS  PubMed  Google Scholar 

  59. Huang N, vom Baur E, Garnier J et al (1998) Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators. EMBO J 17:3398–3412

    Article  CAS  PubMed  Google Scholar 

  60. Angrand P, Apiou F, Stewart AF et al (2001) NSD3, a new SET domain-containing gene, maps to 8p12 and is amplified in human breast cancer cell lines. Genomics 74:79–88

    Article  CAS  PubMed  Google Scholar 

  61. Kurotaki N, Imaizumi K, Harada N et al (2002) Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet 30:365–366

    Article  CAS  PubMed  Google Scholar 

  62. Tatton-Brown K, Rahman N (2006) Sotos syndrome. Eur J Hum Genet 15:264–271

    Article  PubMed  Google Scholar 

  63. Cerveira N, Correia C, Dória S et al (2003) Frequency of NUP98–NSD1 fusion transcript in childhood acute myeloid leukaemia. Leukemia 17:2244–2247

    Article  CAS  PubMed  Google Scholar 

  64. Rosati R, La Starza R, Veronese A et al (2002) NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t (8;11)(p11.2;p15). Blood 99:3857–3860

    Article  CAS  PubMed  Google Scholar 

  65. Wang GG, Cai L, Pasillas MP et al (2007) NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol 9:804–812

    Article  CAS  PubMed  Google Scholar 

  66. Berdasco M, Ropero S, Setien F et al (2009) Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma. Proc Natl Acad Sci 106:21830–21835

    Article  CAS  PubMed  Google Scholar 

  67. Li Y, Trojer P, Xu C et al (2009) The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate. J Biol Chem 284:34283–34295

    Article  CAS  PubMed  Google Scholar 

  68. Nielsen AL, Jorgensen P, Lerouge T et al (2004) Nizp1, a novel multitype zinc finger protein that interacts with the NSD1 histone lysine methyltransferase through a unique C2HR motif. Mol Cell Biol 24:5184–5196

    Article  CAS  PubMed  Google Scholar 

  69. Lu T, Jackson MW, Wang B et al (2010) Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci 107:46–51

    Article  CAS  PubMed  Google Scholar 

  70. Maas NMC, Van Buggenhout G, Hannes F et al (2008) Genotype-phenotype correlation in 21 patients with Wolf–Hirschhorn syndrome using high resolution array comparative genome hybridisation (CGH). J Med Genet 45:71–80

    Article  CAS  PubMed  Google Scholar 

  71. Bergemann A, Cole F, Hirschhorn K (2005) The etiology of Wolf–Hirschhorn syndrome. Trends Genet 21:188–195

    Article  CAS  PubMed  Google Scholar 

  72. Zollino M, Lecce R, Fischetto R et al (2003) Mapping the Wolf–Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet 72:590–597

    Article  CAS  PubMed  Google Scholar 

  73. Wright T, Ricke D, Denison K et al (1997) A transcript map of the newly defined 165 kb Wolf–Hirschhorn syndrome critical region. Hum Mol Genet 6:317–324

    Article  CAS  PubMed  Google Scholar 

  74. Dimmer KS, Navoni F, Casarin A et al (2008) LETM1, deleted in Wolf–Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability. Hum Mol Genet 17:201–214

    Article  CAS  PubMed  Google Scholar 

  75. Simon R, Bergemann AD (2008) Mouse models of Wolf–Hirschhorn syndrome. Am J Med Genet C Semin Med Genet 148C:275–280

    Article  CAS  PubMed  Google Scholar 

  76. Chesi M, Nardini E, Lim RS et al (1998) The t (4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92:3025–3034

    CAS  PubMed  Google Scholar 

  77. Stec I, Wright TJ, van Ommen GJ et al (1998) WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf–Hirschhorn syndrome critical region and is fused to IgH in t (4; 14) multiple myeloma. Hum Mol Genet 7:1071–1082, Published erratum appears in Hum Mol Genet 1998 Sep; 7 (9): 1527

    Article  CAS  PubMed  Google Scholar 

  78. Kang HB, Choi Y, Lee JM et al (2009) The histone methyltransferase, NSD2, enhances androgen receptor-mediated transcription. FEBS Lett 583:1880–1886

    Article  CAS  PubMed  Google Scholar 

  79. 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  Google Scholar 

  80. Kleefstra T, Smidt M, Banning M et al (2005) Disruption of the gene euchromatin histone methyl transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome. J Med Genet 42:299–306

    Article  CAS  PubMed  Google Scholar 

  81. 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 

  82. 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  Google Scholar 

  83. Schaefer A, Sampath SC, Intrator A et al (2009) Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 64:678–691

    Article  CAS  PubMed  Google Scholar 

  84. 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  Google Scholar 

  85. 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 

  86. Ueda J, Tachibana M, Ikura T et al (2006) Zinc finger protein wiz links G9a/GLP histone methyltransferases to the co-repressor molecule CtBP. J Biol Chem 281:20120–20128

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

We thank John A McGrath, Lo Wan Ning, Christine Vogler, and Masaki Mori for their critical reading of the manuscript. This work was supported by grants from Japan Heart Foundation Research Grant and Kanae foundation for the promotion of medical science to K. N.

Disclosure of potential conflict of interests

The authors declare no conflict of interests related to this study.

Author information

Authors and Affiliations

  1. Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Keisuke Nimura, Kiyoe Ura & Yasufumi Kaneda

Authors
  1. Keisuke Nimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kiyoe Ura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasufumi Kaneda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keisuke Nimura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nimura, K., Ura, K. & Kaneda, Y. Histone methyltransferases: regulation of transcription and contribution to human disease. J Mol Med 88, 1213–1220 (2010). https://doi.org/10.1007/s00109-010-0668-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-010-0668-4

Keywords

Search

Navigation