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Interplay between chromatin marks in development and disease

Abstract

DNA methylation (DNAme) and histone post-translational modifications (PTMs) have important roles in transcriptional regulation. Although many reports have characterized the functions of such chromatin marks in isolation, recent genome-wide studies reveal surprisingly complex interactions between them. Here, we focus on the interplay between DNAme and methylation of specific lysine residues on the histone H3 tail. We describe the impact of genetic perturbation of the relevant methyltransferases in the mouse on the landscape of chromatin marks as well as the transcriptome. In addition, we discuss the specific neurodevelopmental growth syndromes and cancers resulting from pathogenic mutations in the human orthologues of these genes. Integrating these observations underscores the fundamental importance of crosstalk between DNA and histone H3 methylation in development and disease.

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Fig. 1: H3K4 methylation inhibits DNMT3A/3B activity.
Fig. 2: H3K9me3 promotes UHRF1 and DNMT1 activity.
Fig. 3: H3K9me3-marked heterochromatin inhibits de novo DNAme in the male germ line.
Fig. 4: H3K36me2 and H3K36me3 recruit DNMT3A/3B.
Fig. 5: Crosstalk between H3K36me2/me3, H3K27me3 and DNAme.

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Acknowledgements

The authors thank A. Bogutz, T. Baubec and J. Majewski for critical reading of the manuscript. This work was supported by CIHR grants PJT-153049 and PJT-166170. The authors apologize to the many colleagues who have made significant contributions to the field but whose work could not be cited or discussed owing to space limitations.

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Glossary

DNA methyltransferases

(DNMTs). A family of enzymes that deposit a methyl group on cytosine DNA nucleotides, mainly in the context of cytosine–guanine dinucleotides.

Transposable elements

(TEs). Also known as ‘jumping genes’, DNA sequences that can insert in new positions in the genome. The vast majority of TEs in the genome are no longer mobile, as they have accumulated mutations over evolutionary time.

CpG islands

(CGIs). Regions in the genome with high GC content that are enriched for CpG dinucleotides.

Imprinted gametic differentially methylated regions

(gDMRs). Regions marked by parent of origin-specific DNA methylation on one of the two parental alleles in the offspring, resulting in monoallelic gene expression. Imprints are established in the parental germ line and maintained after fertilization.

Inner cell mass

(ICM). Pluripotent cells residing in the blastocyst, which can be isolated and cultured in vitro as embryonic stem cells.

Dnmt triple-knockout mESCs

Mouse embryonic stem cells (mESCs) that lack de novo and maintenance DNA methylation owing to genetic deletions of the DNA methyltransferase genes Dnmt3a, Dnmt3b and Dnmt1.

Epiblast

The pluripotent primary lineage that arises from the inner cell mass of the blastocyst.

Bivalent

The dual presence of histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3, mainly found in the promoter regions of developmentally important transcription factors.

Retrotransposons

A class of transposable elements that are transcribed into mRNA and then reverse transcribed into DNA before integrating in the genome.

Krüppel-associated box domain zinc-finger proteins

(KRAB-ZFPs). The largest family of ZFP-based transcription factors in mouse and human genomes.

2i medium

Medium supplemented with leukaemia inhibitory factor and two small-molecule kinase inhibitors (of MEK and GSK3) to establish mouse embryonic stem cells (mESCs) in a naive-like ground state that is characterized by global DNA hypomethylation.

Epiblast-like cells

An in vitro model of epiblast cells. They are derived by culturing mouse embryonic stem cells (mESCs) in the presence of activin A and basic fibroblast growth factor and are characterized by global DNA hypermethylation.

PGC-like cells

An in vitro model of primordial germ cells (PGCs). They are derived by culturing epiblast-like cells in the presence of bone morphogenetic protein, leukaemia inhibitory factor, stem cell factor and epidermal growth factor. They are characterized by global DNA hypomethylation.

DNMT3C

DNA methyltransferase 3C (DNMT3C) is a recently discovered rodent-specific DNMT3 paralogue that is responsible for de novo DNA methylation of evolutionarily young retrotransposons in male germ cells.

Prospermatogonia

(PSG). Quiescent prenatal male germ cells derived from primordial germ cells.

Hutchinson–Gilford progeria syndrome

(HGPS). A premature ageing syndrome caused by a de novo heterozygous mutation in the lamin A (LMNA) gene.

Heterochromatin protein 1

(HP1). A family of three HP1 paralogues (HP1α, HP1β and HP1γ, encoded by CBX5, CBX1 and CBX3 genes, respectively) that can bind to H3K9me2/me3 and are involved in heterochromatin formation and gene silencing.

Partially methylated domains

(PMDs). Large undermethylated, genomic regions localized in heterochromatic/lamina-associated domains. PMDs are generally gene poor and characterized by late replication timing, H3K9me3 enrichment and low CpG density.

Oncohistone

Cancer-associated mutations in histone genes, including H3.1 and H3.3 genes, that affect residues in the histone tail near or overlapping with residues that harbour post-translational modifications in wild-type histones.

DNA methylation valleys

(DMVs). Large genomic regions with low levels of DNA methylation. Also called DNA methylation canyons.

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Janssen, S.M., Lorincz, M.C. Interplay between chromatin marks in development and disease. Nat Rev Genet 23, 137–153 (2022). https://doi.org/10.1038/s41576-021-00416-x

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