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The diverse functions of histone lysine methylation
Nature Reviews Molecular Cell Biologyvolume 6, pages838–849 (2005)Cite this article
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Key Points
DNA is packaged with histone proteins to form chromatin. The histone proteins are subject to numerous covalent modifications that regulate biological processes that are associated with chromatin, such as gene expression.
A number of lysine residues within histones H3 and H4 are subject to methylation by site-specific enzymes. With regard to gene expression, some methylated lysines are involved in activation, whereas others are involved in repression. Current evidence suggests that methylated lysines within histones direct the recruitment of different methyl-binding proteins, which mediate the biological effects of lysine methylation.
The methylation of H3 lysine 9 (H4-K9) and H4-K20 is involved in the formation of heterochromatin, a specific type of chromatin that is necessary for the proper functioning of centromeres and certain recombination events. Although the function of H4-K20 methylation is unclear, the methylation of H3-K9 functions in the recruitment of Swi6 or its mammalian homologue HP1. Recently, it has been demonstrated that the RNA interference pathway is critical for the recruitment of methyltransferases to sites of heterochromatin formation.
The methylation of H3-K9 and H3-K27 has been linked to gene silencing. H3-K9 methylation seems to direct the recruitment of HP1 to several cell-cycle-regulated genes to silence gene expression. H3-K27 methylation is mediated by enzyme complexes composed of members of the Polycomb Group (PcG). PcG proteins have a role in a number of silencing phenomena including homeotic gene silencing, X-inactivation and imprinting.
K4, K36 and K79 within histone H3 are associated with the positive regulation of gene expression. The enzymes that mediate H3-K4 and H3-K36 methylation are associated with the transcriptional machinery, and these modifications are established during transcriptional elongation. H3-K4 methylation has been shown to function as a binding site for severalenzymes that are involved in gene expression, including chromatin remodelling enzymes, histone acetyltransferases and lysine methyltransferases.
Recently, studies have provided convincing evidence that histone lysine methylation can be reversed, thereby providing an additional level of control. LSD1 demethylates H3-K4 and H3-K9 through an amine oxidase reaction and seems to function as both a positive and negative regulator of gene expression.
Abstract
Covalent modifications of histone tails have fundamental roles in chromatin structure and function. One such modification, lysine methylation, has important functions in many biological processes that include heterochromatin formation, X-chromosome inactivation and transcriptional regulation. Here, we summarize recent advances in our understanding of how lysine methylation functions in these diverse biological processes, and raise questions that need to be addressed in the future.
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Acknowledgements
We would like to thank the referees for their helpful comments. We apologize to our colleagues for not being able to quote all references due to limitations in space. Work in the Zhang laboratory is supported by the National Institutes of Health.
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Department of Biochemistry & Biophysics, Howard Hughes Medical Institute, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, 27599-7295, USA
Cyrus Martin & Yi Zhang
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- Yi Zhang
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Correspondence toYi Zhang.
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Glossary
- SET DOMAIN
A sequence motif (named after Su(var)3–9, Enhancer of Zeste, Trithorax) that is found in several chromatin-associated proteins, including members of both the Trithorax group (trxG) and Polycomb group (PcG).
- X INACTIVATION
A process of dosage compensation in mammals that is achieved by the transcriptional silencing of one of the X chromosomes in XX females.
- BROMODOMAIN
A conserved acetyl-lysine binding domain found in several transcriptional regulatory proteins that are involved in gene activation.
- CHROMODOMAIN
A conserved protein structure that is common to some chromosomal proteins. It interacts with chromatin by binding to methylated lysine residues in histone proteins.
- TUDOR DOMAIN
A conserved protein domain that is found in several RNA-binding proteins and chromatin-associated proteins. Recent studies indicate this domain can bind to methyl-lysine or methyl-arginine.
- WD40-REPEAT DOMAIN
A protein motif that is composed of a 40-amino-acid repeat that forms a β-propeller sheet. Proteins that contain WD40 repeats function in a wide range of cellular functions, including G-protein-mediated signal transduction, transcriptional regulation, RNA processing, and regulation of vesicle formation and trafficking.
- CENTROMERE
Region of a chromosome that is attached to the spindle during nuclear division.
- TELOMERE
A segment at the end of each chromosome arm that consists of a series of repeated DNA sequences.
- MATING-TYPE SWITCHING
A recombination event occurring in yeast that results in a 'switch' from one mating type, or sex, to another.
- POSITION EFFECT VARIEGATION
A type of gene silencing that results from the translocation of normally active genes to locations that are proximal to heterochromatin. Silencing is initiated in a stochastic manner, but, once established, is stable and results in a variegated expression pattern.
- SMALL INTERFERING RNA
(siRNA). A non-coding RNA (∼22 nucleotides long) that is derived from the processing of long double-stranded RNA during RNA interference. siRNAs direct the destruction or translation repression of mRNA targets that they hybridize with.
- EUCHROMATIN
A form of chromatin that is decondensed during interphase and that contains actively transcribing genes.
- GENOMIC IMPRINTING
A genetic mechanism by which genes are selectively expressed from the maternal or paternal chromosomes.
- POLYCOMB GROUP
(PcG). A class of proteins — originally described inDrosophila melanogaster — that maintain stable and heritable repression of a number of genes, including the homeotic genes with which they are associated.
- HOX GENES
(Homeobox genes). A group of linked regulatory genes that are involved in patterning the animal body axis during development.
- UBIQUITIN E3 LIGASE
An enzyme that catalyses the covalent attachment of ubiquitin to lysine residues in proteins.
- HISTONE DEACETYLASES
Enzymes that modify histones by removing acetyl groups, a chemical modification that is implicated in the regulation of gene expression and chromatin structure.
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Martin, C., Zhang, Y. The diverse functions of histone lysine methylation.Nat Rev Mol Cell Biol6, 838–849 (2005). https://doi.org/10.1038/nrm1761
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