Key Points
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Methylation occurs on various basic residues on histones and depending on the degree of methylation and the location of the methylated residue, there are different functional outcomes.
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Histone methylation is a dynamic process, and methyl marks can be added or removed by specific enzymes. Other proteins can recognize and bind methylated residues to effect phenotypic outcomes.
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Histone-modifying enzymes can be recruited to specific loci by DNA sequence, non-coding RNA, DNA methylation or other post-translational marks on histone tails.
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Histone methylation can be dynamic or stable through the life of a cell and even through mitosis and meiosis and can, on some occasions, be inherited from parents to children.
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Histone methylation helps to explain our phenotypic diversity from cell to cell and when its regulation and the balance between stable and dynamic marks are altered, diseases such as cancer and intellectual disability can ensue.
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Histone methylation has been shown to have a role in almost all biological processes from DNA repair, cell cycle, stress response and transcription to development, differentiation and ageing.
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Histone methylation levels change with age, and methyltransferases and demethylases have been shown to regulate longevity of several model organisms. In some instances, these enzymes have been shown to have a transgenerational effect on lifespan.
Abstract
Organisms require an appropriate balance of stability and reversibility in gene expression programmes to maintain cell identity or to enable responses to stimuli; epigenetic regulation is integral to this dynamic control. Post-translational modification of histones by methylation is an important and widespread type of chromatin modification that is known to influence biological processes in the context of development and cellular responses. To evaluate how histone methylation contributes to stable or reversible control, we provide a broad overview of how histone methylation is regulated and leads to biological outcomes. The importance of appropriately maintaining or reprogramming histone methylation is illustrated by its links to disease and ageing and possibly to transmission of traits across generations.
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Acknowledgements
We thank E. Pollina for critical reading of the manuscript. We thank P. Trojer and M. T. Bedford for helpful discussions. The work from the Shi laboratory is supported by grants from the US National Institutes of Health (GM058012, GM071004 and NCI118487). E.L.G. was supported by a Helen Hay Whitney postdoctoral fellowship. We apologize for literature omitted owing to space limitations.
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Glossary
- Symmetrically dimethylated
-
Symmetrically dimethylated arginines have methyl groups on each of the two nitrogens.
- Asymmetrically dimethylated
-
Asymmetrically dimethylated arginines have two methyl groups on a single nitrogen.
- Trithorax group proteins
-
(TrxG proteins). A group of chromatin regulatory proteins that typically act to activate or to maintain gene expression.
- Polycomb group proteins
-
(PcG proteins). Chromatin regulatory proteins that are typically involved in repressing gene expression.
- Polycomb repressive complex 2
-
(PRC2). A Polycomb group complex that trimethylates histone H3 lysine 27 (H3K27). The core PRC2 subunits are SUZ12, EED and the methyltransferases EZH2 (E(Z) in Drosphila melanogaster); there are additional components as well.
- RNAi
-
A series of processes in which small RNAs (that are in complexes with proteins) bind to specific mRNA molecules or to genes and can regulate their activity.
- X-chromosome inactivation
-
A mechanism for silencing one of the two X chromosomes in female mammals to compensate for the different gene dosage in XX females and XY males. Heterochromatin forms on the inactive X chromosome.
- MLL complex
-
A protein complex containingmixed-lineage leukaemia or myeloid/lymphoid (MLL) proteins, which are the mammalian homologues of Trithorax and have methyltransferase activity.
- PHD fingers
-
Plant homeo domains are nuclear Zn2+-binding domains ranging from ~50–80 amino acids and typically have a signature of four cysteines, one histidine and three cysteines. They bind to both histone and non-histone proteins and, in some cases, function as E3 ligases.
- WD40 repeats
-
A short ~40 amino acid domain usually terminating in tryptophan (W) and aspartic acid (D), which forms a circularized beta-propeller structure. They can serve as scaffolding proteins for multiprotein complexes.
- CW domains
-
A ~45–55 amino acid zinc-binding domain containing at least four cysteine (C) and two tryptophan (W) residues that are exclusively found in eukaryotes.
- PWWP domains
-
These ~135 amino acid domains have a central core consisting of proline tryptophan tryptophan proline (PWWP) and are found in eukaryotes from yeast to mammals. The PWWP domain has a barrel-like five-stranded structure and a five-helix bundle.
- MBT
-
A royal superfamily domain that binds to methylated lysine.
- ADD domain
-
This domain is named after its presence in three proteins ATRX, DNMT3 and DNMT3L, which bind to histone H3. It contains a GATA-like C2C2 zinc finger and a C4C4 imperfect PHD finger. It contains ~120 amino acids.
- Pre-initiation complex
-
A large complex of proteins that is necessary for the transcription of protein-coding genes. It helps to position RNA polymerase II appropriately and to orient the DNA in the active site of RNA polymerase II.
- Small nuclear ribonucleoprotein
-
(snRNP). These are RNA–protein complexes that, together with other proteins and precursor mRNA, form a complex where splicing occurs.
- Stable isotope labelling by amino acids in cell culture
-
(SILAC). Two cell populations (an experimental one and a control one) that have been grown in media containing only heavy or only light forms of particular amino acids can be compared by quantitative mass spectrometry proteomics.
- Epigenetic
-
In this context, we use the term 'epigenetic' to refer to heritable changes in gene expression that occur without alterations in DNA sequence.
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Greer, E., Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 13, 343–357 (2012). https://doi.org/10.1038/nrg3173
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DOI: https://doi.org/10.1038/nrg3173
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