Abstract
Histone methylation can occur at various sites in histone proteins, primarily on lysine and arginine residues, and it can be governed by multiple positive and negative regulators, even at a single site, to either activate or repress transcription. It is now apparent that histone methylation is critical for almost all stages of development, and its proper regulation is essential for ensuring the coordinated expression of gene networks that govern pluripotency, body patterning and differentiation along appropriate lineages and organogenesis. Notably, developmental histone methylation is highly dynamic. Early embryonic systems display unique histone methylation patterns, prominently including the presence of bivalent (both gene-activating and gene-repressive) marks at lineage-specific genes that resolve to monovalent marks during differentiation, which ensures that appropriate genes are expressed in each tissue type. Studies of the effects of methylation on embryonic stem cell pluripotency and differentiation have helped to elucidate the developmental roles of histone methylation. It has been revealed that methylation and demethylation of both activating and repressive marks are essential for establishing embryonic and extra-embryonic lineages, for ensuring gene dosage compensation via genomic imprinting and for establishing body patterning via HOX gene regulation. Not surprisingly, aberrant methylation during embryogenesis can lead to defects in body patterning and in the development of specific organs. Human genetic disorders arising from mutations in histone methylation regulators have revealed their important roles in the developing skeletal and nervous systems, and they highlight the overlapping and unique roles of different patterns of methylation in ensuring proper development.
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Change history
07 November 2019
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Acknowledgements
Research in the Shi lab is supported by grants from the US National Institutes of Health (RO1 GM117264, RO1 MH096066, R35 CA210104). Y.S. is an American Cancer Society Research Professor.
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All authors made substantial contributions to the discussion of content, wrote the manuscript and edited it before submission. A.J. and A.D. also researched data for the article.
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Y.S. is a cofounder of Constellation Pharmaceuticals and Athelas Therapeutics, as well as a consultant for Active Motif, Inc. A.J. and A.D. declare no competing interests.
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Glossary
- Genomic imprinting
-
Monoallelic expression of a gene specifically from either the maternal or paternal copy.
- HOX genes
-
Genes encoding homeodomain-containing developmental transcription factors that are arranged in linear arrays and expressed in a spatially and temporally regulated manner corresponding to their one-dimensional arrangement along the chromosome.
- Chromodomain
-
Protein domain that binds methylated lysine.
- Bromodomain
-
Protein domain that binds acetylated lysine.
- SET domain
-
Protein domain that typically harbours catalytic methyltransferase activity.
- Plant homeodomain (PHD) fingers
-
Zinc-finger-containing domain involved in recognizing histone modifications.
- Tudor domain
-
Protein domain that recognizes methylated lysines and arginines.
- CpG islands
-
Regions of the genome with elevated frequency of CpG dinucleotide, often occurring in gene regulatory regions and often displaying DNA hypomethylation on cytosine.
- Mid-blastula transition
-
Embryonic stage at which cells in the blastula switch from rapid cycling between S and M phases to lengthened cell cycles including G1 and G2 phases.
- Trophectoderm
-
Cells forming the outer layer of the mammalian embryo that later give rise to the placenta.
- Inner cell mass
-
Cluster of undifferentiated cells in the mammalian embryo that give rise to the fetus.
- Poised enhancers
-
Enhancers that contain H3K4me1 and H3K27me3 marks and are unable to activate gene expression but that remain capable of activation in the future.
- Primed enhancers
-
An enhancer state that is intermediate between poised and active states. Such enhancers are characterized by H3K4me1 marks and DNA hypomethylation but are unable to activate gene expression.
- Zygotic gene activation
-
Activation of transcription from the genome of the embryo, accompanied by clearance of maternal transcripts.
- Sex combs
-
In Drosophila melanogaster, a set of male-specific bristles on the leg.
- Position effect variegation
-
Variation in gene expression levels based on the surrounding genomic context of the gene.
- Neural crest cells
-
Embryonic cells that arise from the ectoderm and give rise to multiple tissues, including craniofacial structures and peripheral nerves.
- Sub-ventricular zone
-
Region of the brain lining the ventricles that generates neural and glial precursors.
- Medulloblastoma
-
Paediatric brain tumour, believed to originate from primitive (undifferentiated) neuro-ectodermal cells, that most commonly arises in the cerebellum during the first decade of life and accounts for approximately 10% of primary brain tumours in children.
- Alu elements
-
Short stretches of DNA containing the AluI restriction site that are repeated millions of times throughout the human genome.
- Embryoid bodies
-
Aggregates of pluripotent cells that contain cells differentiating towards each of the three germ layers.
- Microcephaly
-
Reduced head circumference.
- Protocadherins
-
Family of cell adhesion proteins important for the development of neurons.
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Jambhekar, A., Dhall, A. & Shi, Y. Roles and regulation of histone methylation in animal development. Nat Rev Mol Cell Biol 20, 625–641 (2019). https://doi.org/10.1038/s41580-019-0151-1
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DOI: https://doi.org/10.1038/s41580-019-0151-1
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