Abstract
Heterochromatin is characterized by dimethylated or trimethylated histone H3 Lys9 (H3K9me2 or H3K9me3, respectively) and is found at transposable elements, satellite repeats and genes, where it ensures their transcriptional silencing. The histone methyltransferases (HMTs) that methylate H3K9 — in mammals Suppressor of variegation 3–9 homologue 1 (SUV39H1), SUV39H2, SET domain bifurcated 1 (SETDB1), SETDB2, G9A and G9A-like protein (GLP) — and the ‘readers’ of H3K9me2 or H3K9me3 are highly conserved and show considerable redundancy. Despite their redundancy, genetic ablation or mistargeting of an individual H3K9 methyltransferase can correlate with impaired cell differentiation, loss of tissue identity, premature aging and/or cancer. In this Review, we discuss recent advances in understanding the roles of the known H3K9-specific HMTs in ensuring transcriptional homeostasis during tissue differentiation in mammals. We examine the effects of H3K9-methylation-dependent gene repression in haematopoiesis, muscle differentiation and neurogenesis in mammals, and compare them with mechanistic insights obtained from the study of model organisms, notably Caenorhabditis elegans and Drosophila melanogaster. In all these organisms, H3K9-specific HMTs have both unique and redundant roles that ensure the maintenance of tissue integrity by restricting the binding of transcription factors to lineage-specific promoters and enhancer elements.
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Acknowledgements
The authors apologize to all those whose articles could not be cited due to space limitations, and they recognize that there are many studies on histone methyltransferases and mammalian cell differentiation beyond those cited here. The authors thank the Friedrich Miescher Institute for Biomedical Research for an excellent research infrastructure and all members of the epigenetics and quantitative biology sections for interaction and discussion. S.M.G. thanks the European Research Council for support through the European Union’s Horizon 2020 research and innovation programme (Epiherigans — agreement no. 743312). J.P. and S.P.M. were both supported by EMBO long-term fellowships in the Gasser laboratory.
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Glossary
- Constitutive heterochromatin
-
Traditional designation of dimethylated or trimethylated H3 Lys9 chromatin that is generally transcriptionally inactive in a manner that persists throughout the cell cycle and throughout development. This chromatin type is neither cell type-specific nor regulated during development.
- Histone methyltransferases
-
(HMTs). Class of enzymes that transfer methyl groups from S-adenosyl-l-methionine to Lys and Arg amino acids, predominantly in histones.
- Facultative heterochromatin
-
Transcriptionally silent chromatin with dimethylated or trimethylated H3 Lys9, which is repressed in a cell type-specific manner that is regulated during development.
- Short interspersed nuclear elements
-
(SINEs). Abundant non-autonomous non-long-terminal-repeat retrotransposons that hijack long interspersed nuclear element proteins to mobilize.
- Argonaute
-
A class of small single-stranded RNA-binding proteins implicated in small RNA-mediated gene silencing.
- Chromocentres
-
In some cells, clustering of centromeric satellite DNA in the nucleus, representing centromeres of multiple chromosomes.
- Endogenous retroviruses
-
(ERVs). Proviral remnants of ancient retroviral infections. Full-length ERVs encode viral proteins such as envelope proteins (env), polymerases (pol) and structural proteins (gag) that can mediate ERV amplification and in some cases encode full viral particles.
- Intracisternal A-particles
-
(IAPs). A rodent-specific class of transposable elements that retain the ability to undergo transposition. Among the most mutagenic long terminal repeat retrotransposons in mice.
- Long interspersed nuclear elements
-
(LINEs). Autonomous non-long-terminal-repeat retrotransposons that constitute the largest transposable element class in human and mice.
- PIWI-interacting RNAs
-
Germline-specific small RNAs that mediate homology-dependent silencing through their interaction with PIWI-clade Argonaute proteins.
- Long terminal repeat
-
(LTR). A direct repeat flanking the coding sequences of LTR retrotransposons, containing regulatory elements and polyadenylation signals. They promote transcription of the retrotransposons and potentially of neighbouring genes.
- Imprinting control regions
-
Genomic regions that epigenetically regulate parental-specific or maternal-specific allelic expression of genes established during germline development.
- R-loops
-
RNA–DNA hybrids formed through hybridization of one of the DNA strands with a complementary RNA, forming a potentially mutagenic structure.
- Assay for transposase-accessible chromatin with high-throughput sequencing
-
(ATAC–seq). A method for monitoring accessibility of chromatin in intact cells. The hyperactive transposase Tn5 is expressed endogenously, and high-throughput sequencing is used to detect sites of transposase cleavage and thus assess levels of accessibility.
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Padeken, J., Methot, S.P. & Gasser, S.M. Establishment of H3K9-methylated heterochromatin and its functions in tissue differentiation and maintenance. Nat Rev Mol Cell Biol 23, 623–640 (2022). https://doi.org/10.1038/s41580-022-00483-w
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DOI: https://doi.org/10.1038/s41580-022-00483-w
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