Targets of histone H3 lysine 9 methyltransferases

Abstract

Histone H3 lysine 9 di- and trimethylation are well-established marks of constitutively silenced heterochromatin domains found at repetitive DNA elements including pericentromeres, telomeres, and transposons. Loss of heterochromatin at these sites causes genomic instability in the form of aberrant DNA repair, chromosome segregation defects, replication stress, and transposition. H3K9 di- and trimethylation also regulate cell type-specific gene expression during development and form a barrier to cellular reprogramming. However, the role of H3K9 methyltransferases extends beyond histone methylation. There is a growing list of non-histone targets of H3K9 methyltransferases including transcription factors, steroid hormone receptors, histone modifying enzymes, and other chromatin regulatory proteins. Additionally, two classes of H3K9 methyltransferases modulate their own function through automethylation. Here we summarize the structure and function of mammalian H3K9 methyltransferases, their roles in genome regulation and constitutive heterochromatin, as well as the current repertoire of non-histone methylation targets including cases of automethylation.

Keywords: chromatin; heterochromatin; histone; methylation; methyltransferase.

FIGURE 1

Structure of the conserved core catalytic SET domain of H3K9 methyltransferases. Structure of the first SET domain to be determined, Dim-5 an H3K9 methyltransferase from Neurospora crassa, in complex with cofactor (white) and histone peptide substrate (red) (PDB ID 1PEG) (left). Close up of conserved cysteines and triangular zinc cluster of the pre-SET domain (top right). Close up of active site (bottom right). The Hinge, pre-SET, SET, SET-I, and post-SET domains are coloured dark blue, green, grey, yellow, and light blue, respectively. Zinc atoms are depicted as dark grey spheres.

FIGURE 2

Domain architecture of the main human H3K9 methyltransferases. Domain architecture of SUV39H1, SUV39H2, SETDB1, SETDB2, G9a, and GLP (Apweiler et al., 2004; Wu et al., 2010; Torrano et al., 2019; Weirich et al., 2021). Domain boundaries are listed above each domain with chromodomain, pre-SET, SET, SET-I, post-SET, Tudor, MBD, and Ankyrin repeat domains coloured grey, light blue, blue, diagonal hatching, dark blue, orange, green, and yellow, respectively.

FIGURE 3

Methylation states catalyzed by main mammalian H3K9 methyltransferases. SUV39H1, SUV39H2, SETDB1, SETDB2, G9a, and GLP transfer methyl groups (red) from cofactor SAM to the epsilon nitrogen (blue) of lysine residues to create mono-, di-, and trimethyllysine.

FIGURE 4

H3K9me3 enrichment at pluripotency versus cell type-specific genes throughout development. In early, pre-implantation stages, H3K9me3 is missing from pluripotency genes but highly enriched at cell type-specific genes, which promotes the pluripotency program. As development proceeds into the germ layer stage, H3K9me3 is deposited at pluripotency genes and becomes significantly lost at cell type-specific genes during lineage commitment to promote tissue specificity. H3K9me3 differentially regulates pluripotency and cell type-specific genes to orchestrate the timely progression of developmental processes.

FIGURE 5

Clr4 automethylation-induced conformational switch. Structure of the autoinhibited (left; PDB ID 6BOX) and automethylated (right; PDB ID 6BP4) Clr4 catalytic domains with domains coloured the same as Figure 1 with the autoregulatory loop coloured red.