Histone Lysine Methylation Dynamics: Establishment, Regulation, and Biological Impact

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Dec 4

PMID 23200123

Citations 595

Authors

Joshua C Black

Capucine Van Rechem

Johnathan R Whetstine

Affiliations

Soon will be listed here.

Abstract

Histone lysine methylation has emerged as a critical player in the regulation of gene expression, cell cycle, genome stability, and nuclear architecture. Over the past decade, a tremendous amount of progress has led to the characterization of methyl modifications and the lysine methyltransferases (KMTs) and lysine demethylases (KDMs) that regulate them. Here, we review the discovery and characterization of the KMTs and KDMs and the methyl modifications they regulate. We discuss the localization of the KMTs and KDMs as well as the distribution of lysine methylation throughout the genome. We highlight how these data have shaped our view of lysine methylation as a key determinant of complex chromatin states. Finally, we discuss the regulation of KMTs and KDMs by proteasomal degradation, posttranscriptional mechanisms, and metabolic status. We propose key questions for the field and highlight areas that we predict will yield exciting discoveries in the years to come.

Citing Articles

Colorectal Cancer: Pathogenesis and Targeted Therapy.

Li J, Pan J, Wang L, Ji G, Dang Y MedComm (2020). 2025; 6(3):e70127.

PMID: 40060193 PMC: 11885891. DOI: 10.1002/mco2.70127.

Potential mechanism of circKIAA1429 accelerating the progression of hepatocellular carcinoma.

Yuan Y, Huang J, Wei G, Hu G, Yu H, Tao Y Infect Agent Cancer. 2025; 20(1):12.

PMID: 40025575 PMC: 11872318. DOI: 10.1186/s13027-025-00645-3.

Melatonin Modulates ZAP70 and CD40 Transcripts via Histone Modifications in Canine Ileum Epithelial Cells.

Hong J, Adam S, Wang S, Huang H, Kim I, Ahmed A Vet Sci. 2025; 12(2).

PMID: 40005847 PMC: 11860356. DOI: 10.3390/vetsci12020087.

Potent and selective SETDB1 covalent negative allosteric modulator reduces methyltransferase activity in cells.

Uguen M, Shell D, Silva M, Deng Y, Li F, Szewczyk M Nat Commun. 2025; 16(1):1905.

PMID: 39994194 PMC: 11850789. DOI: 10.1038/s41467-025-57005-3.

Heterochromatin fidelity is a therapeutic vulnerability in lymphoma and other human cancers.

Najia M, Jha D, Zhang C, Laurent B, Kubaczka C, Markel A bioRxiv. 2025; .

PMID: 39975048 PMC: 11838449. DOI: 10.1101/2025.01.31.635709.

References

Herranz N, Dave N, Millanes-Romero A, Morey L, Diaz V, Lorenz-Fonfria V . Lysyl oxidase-like 2 deaminates lysine 4 in histone H3. Mol Cell. 2012; 46(3):369-76. DOI: 10.1016/j.molcel.2012.03.002. View

Shi Y, Sawada J, Sui G, Affar E, Whetstine J, Lan F . Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature. 2003; 422(6933):735-8. DOI: 10.1038/nature01550. View

Towbin B, Gonzalez-Aguilera C, Sack R, Gaidatzis D, Kalck V, Meister P . Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery. Cell. 2012; 150(5):934-47. DOI: 10.1016/j.cell.2012.06.051. View

Jenuwein T . The epigenetic magic of histone lysine methylation. FEBS J. 2006; 273(14):3121-35. DOI: 10.1111/j.1742-4658.2006.05343.x. View

Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield V . hDOT1L links histone methylation to leukemogenesis. Cell. 2005; 121(2):167-78. DOI: 10.1016/j.cell.2005.02.020. View

Kouzarides T . Chromatin modifications and their function. Cell. 2007; 128(4):693-705. DOI: 10.1016/j.cell.2007.02.005. View

Garcia-Cao M, OSullivan R, Peters A, Jenuwein T, Blasco M . Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat Genet. 2004; 36(1):94-9. DOI: 10.1038/ng1278. View

Zhang X, Tamaru H, Khan S, Horton J, Keefe L, Selker E . Structure of the Neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase. Cell. 2002; 111(1):117-27. PMC: 2713760. DOI: 10.1016/s0092-8674(02)00999-6. View

Smith E, Shilatifard A . The chromatin signaling pathway: diverse mechanisms of recruitment of histone-modifying enzymes and varied biological outcomes. Mol Cell. 2010; 40(5):689-701. PMC: 3037032. DOI: 10.1016/j.molcel.2010.11.031. View

10.

Tzatsos A, Paskaleva P, Lymperi S, Contino G, Stoykova S, Chen Z . Lysine-specific demethylase 2B (KDM2B)-let-7-enhancer of zester homolog 2 (EZH2) pathway regulates cell cycle progression and senescence in primary cells. J Biol Chem. 2011; 286(38):33061-9. PMC: 3190920. DOI: 10.1074/jbc.M111.257667. View

11.

Nagano T, Mitchell J, Sanz L, Pauler F, Ferguson-Smith A, Feil R . The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science. 2008; 322(5908):1717-20. DOI: 10.1126/science.1163802. View

12.

Carrozza M, Li B, Florens L, Suganuma T, Swanson S, Lee K . Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell. 2005; 123(4):581-92. DOI: 10.1016/j.cell.2005.10.023. View

13.

Kantojarvi K, Onkamo P, Vanhala R, Alen R, Hedman M, Sajantila A . Analysis of 9p24 and 11p12-13 regions in autism spectrum disorders: rs1340513 in the JMJD2C gene is associated with ASDs in Finnish sample. Psychiatr Genet. 2010; 20(3):102-8. DOI: 10.1097/YPG.0b013e32833a2080. View

14.

Sampath S, Marazzi I, Yap K, Sampath S, Krutchinsky A, Mecklenbrauker I . Methylation of a histone mimic within the histone methyltransferase G9a regulates protein complex assembly. Mol Cell. 2007; 27(4):596-608. DOI: 10.1016/j.molcel.2007.06.026. View

15.

Tsukada Y, Fang J, Erdjument-Bromage H, Warren M, Borchers C, Tempst P . Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2005; 439(7078):811-6. DOI: 10.1038/nature04433. View

16.

Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M . G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 2002; 16(14):1779-91. PMC: 186403. DOI: 10.1101/gad.989402. View

17.

Huang J, Berger S . The emerging field of dynamic lysine methylation of non-histone proteins. Curr Opin Genet Dev. 2008; 18(2):152-8. DOI: 10.1016/j.gde.2008.01.012. View

18.

Greer E, Shi Y . Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012; 13(5):343-57. PMC: 4073795. DOI: 10.1038/nrg3173. View

19.

Huang S . Histone methyltransferases, diet nutrients and tumour suppressors. Nat Rev Cancer. 2002; 2(6):469-76. DOI: 10.1038/nrc819. View

20.

Hnilicova J, Stanek D . Where splicing joins chromatin. Nucleus. 2011; 2(3):182-8. PMC: 3149878. DOI: 10.4161/nucl.2.3.15876. View