Abstract
The precise regulation of gene transcription is required to establish and maintain cell type-specific gene expression programs during multicellular development. In addition to transcription factors, chromatin, and its chemical modification, play a central role in regulating gene expression. In vertebrates, DNA is pervasively methylated at CG dinucleotides, a modification that is repressive to transcription. However, approximately 70% of vertebrate gene promoters are associated with DNA elements called CpG islands (CGIs) that are refractory to DNA methylation. CGIs integrate the activity of a range of chromatin-regulating factors that can post-translationally modify histones and modulate gene expression. This is exemplified by the trimethylation of histone H3 at lysine 4 (H3K4me3), which is enriched at CGI-associated gene promoters and correlates with transcriptional activity. Through studying H3K4me3 at CGIs it has become clear that CGIs shape the distribution of H3K4me3 and, in turn, H3K4me3 influences the chromatin landscape at CGIs. Here we will discuss our understanding of the emerging relationship between CGIs, H3K4me3, and gene expression.
Highlights
The precise control of gene transcription is required for cellular homeostasis and to establish the cell type-specific gene expression patterns that are necessary for complex multicellular development
This suggests that the SET1A/B complexes are targeted to CpG islands (CGIs)-associated gene promoters via recognition of non-methylated CpG DNA by the Zinc Finger (ZF)-CxxC domain of CFP1
Given that the abnormal methylation of CGI gene promoters is associated with stable transcriptional repression, for example in cancer, it has been proposed that the non-methylated state of CGIs contributes to the maintenance of a chromatin environment that is responsive to gene regulatory cues [136,137,138,139]
Summary
The precise control of gene transcription is required for cellular homeostasis and to establish the cell type-specific gene expression patterns that are necessary for complex multicellular development. While the enrichment of H3K4me at gene promoters is conserved across all eukaryotes, in vertebrates H3K4me is more broadly distributed and enriched at enhancers, while H3K4me tends to be elevated in regions flanking peaks of H3K4me (Fig. 1B) [8,9,10,11] In line with these more diverse patterns of H3K4 methylation, in higher eukaryotes there is an expanded repertoire of enzymes that deposit these modifications. Analogous to the functional organisation of the H3K4 HMTs in Drosophila, mammalian MLL3/4 complexes are typically associated with H3K4me deposition at enhancers, while SET1A/B and MLL1/2 complexes define H3K4me2/3 at gene promoters [21,22,23,24,25,26,27] These H3K4 HMT complexes share a subset of accessory factors but are distinguished based on the identity of their catalytic subunit and are further functionally specialised by the incorporation of complex-specific factors [28] (Fig. 1C and reviewed in Shilatifard [14]).
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