Roles and regulation of histone methylation in animal development

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.

Fig. 1 |. Examples of regulation of gene expression by histone methyltransferases and demethylases.

SETD1A methyltransferase complex (comprising SETD1A (a catalytic SET-domain subunit), together with the binding partners ASH2L, RBBP5, WDR5 and other complex-specific subunits not shown) deposits the gene-activating H3 Lys4 tri-methyl (H3K4me3) mark at the promoters of various genes. H3K4me3 is recognized by PHD finger domains in proteins such as TAF3, which bind to methylated Lys. Gene activation can be reversed through the removal of this modification by the demethylase KDM5C, which utilizes α-ketoglutarate (αKG) as a cofactor. Gene-repressive states can be established by the deposition of H3K9me3 by the SETDB1 histone methyltransferase complex (including the catalytic subunit SETDB1 together with a regulator, MCAF (also known as ATF7IP) and a reader protein, TRIM28). H3K9me3 is recognized by the chromodomain in HP1 proteins and can be removed by the KDM3A and/or KDM3B demethylase in the presence of αKG as a cofactor, to allow for gene activation.

Fig. 2 |. The importance of histone methylation regulators in mammalian development and organogenesis.

a | Mouse developmental stages at which null alleles of the indicated histone methylation regulators exhibit embryonic lethality. Loss of some histone methylation regulators causes very early lethality, before or during implantation (for example, SETDB1), whereas other regulators are required at later stages of organogenesis, with the majority exhibiting lethality between embryonic day 7 (E7) and E12. For some regulators (MLL1, SETDB1), lethality was observed at different stages, depending on the report, in which case all reports are shown. For references to the relevant reports, see Supplementary Table 1. b | Tissue-specific sites of action of histone methylation regulators, as revealed by conditional knockout analysis or by analysis of viable systemic knockouts in mice. Many regulators are essential for neurodevelopment and cardiac development, whereas others regulate myogenesis, adipogenesis and haematopoiesis. For references to the relevant reports, see Supplementary Table 2. ICM, inner cell mass.

Fig. 3 |. Developmental processes regulated by histone methylation.

a | Genomic imprinting is mediated by both histone and DNA methylation. Paternally expressed genes display undetectable or very low levels of repressive DNA and H3K27 methylation marks. The maternal allele is silenced either by DNA methylation, introduced by DNA methyltransferases (DNMTs), or, in regions of hypomethylated DNA, by tri-methylation of Lys27 of histone H3 (H3K27me3), introduced by the PRC2 complex. The predominant mechanism for the silencing of imprinted genes varies by the locus. b | Regulation of HOX genes by histone methylation. In embryonic stem cells (ESCs), histone tri-methylation at H3K27 represses all HOX genes. At later stages of differentiation, early HOX genes are activated along the anterior–posterior axis by removal of H3K27me3 and addition of H3K4me3. Subsequently, late HOX genes are activated in caudal regions by a similar mechanism. In differentiated cells, HOX genes are again repressed by tri-methylation at H3K9 and H3K27. It is not known whether these methylation marks occur on the same or separate nucleosomes. c | Effects of histone methylation regulators on ESC self-renewal and differentiation. Although some regulators directly influence ESC self-renewal (SETDB1, WDR5, SETD1A, G9a), most affect the ability of ESCs to differentiate (as assessed by using embryoid body formation assays, which indicate the ability to form the three germ layers, or by various differentiation-inducing protocols (including those that direct ESCs towards a particular lineage)). In cases where different studies have indicated divergent roles, all outcomes are listed. For references to the relevant reports, see Supplementary Table 3.