Abstract
SummaryChromatin modifications and the promoter-associated epigenome are important for the regulation of gene expression. However, the mechanisms by which chromatin-modifying complexes are targeted to the appropriate gene promoters in vertebrates and how they influence gene expression have remained poorly defined. Here, using a combination of live-cell imaging and functional genomics, we discover that the vertebrate SET1 complex is targeted to actively transcribed gene promoters through CFP1, which engages in a form of multivalent chromatin reading that involves recognition of non-methylated DNA and histone H3 lysine 4 trimethylation (H3K4me3). CFP1 defines SET1 complex occupancy on chromatin, and its multivalent interactions are required for the SET1 complex to place H3K4me3. In the absence of CFP1, gene expression is perturbed, suggesting that normal targeting and function of the SET1 complex are central to creating an appropriately functioning vertebrate promoter-associated epigenome.
Highlights
Gene expression is controlled by transcription factors that bind to DNA sequences in gene regulatory elements and control how RNA polymerase engages with transcription start sites (Levine et al, 2014)
This is based on work that described CFP1 occupancy at CpG islands (CGIs) elements (Denissov et al, 2014; Thomson et al, 2010) and defects in H3K4me3 resulting from its deletion in embryonic stem cells (ESCs) (Carlone et al, 2005; Clouaire et al, 2012, 2014; Tate et al, 2009)
How CFP1 dynamics and chromatin binding are achieved in vivo, and whether these are central determinants in guiding the SET1 complex to genomic target sites, remains largely unknown
Summary
Gene expression is controlled by transcription factors that bind to DNA sequences in gene regulatory elements and control how RNA polymerase engages with transcription start sites (Levine et al, 2014). Post-translational modifications on histones at gene regulatory elements can alter chromatin structure or recruit reader proteins that regulate access to DNA and help to shape gene expression (Piunti and Shilatifard, 2016; Venkatesh and Workman, 2015). The SET1 complexes are the predominant H3K4 methyltransferases (Ardehali et al, 2011; Bledau et al, 2014; Hallson et al, 2012) and H3K4me is thought to act as a nucleation site for binding of reader proteins that elicit effects on chromatin structure and gene regulation (Lauberth et al, 2013; Li et al, 2006; Pena et al, 2006; Shi et al, 2006; Vermeulen et al, 2007; Wysocka et al, 2006). Deletion of SET1A in mice results in early embryonic lethality due to a failure of embryos to gastrulate, illustrating a fundamental role for the SET1A complex in mammalian development (Bledau et al, 2014)
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