More than half of the human genome is comprised of EREs of various types. Appropriate control of their activity is crucial not only for limiting insertional mutagenesis (for the subset of EREs that are mobilization competent) but also because EREs can function as cis-regulatory elements to influence the expression of nearby cellular genes to modulate cell behaviour and differentiation potential. An emerging theme is that in human and mouse ESCs many EREs remain silenced, whereas others become transiently and selectively derepressed, and their transcripts have active roles in maintaining the pluripotent state.
TRIM28 (also known as KAP1 and TIF1β) is a transcriptional corepressor that is brought to genomic sites by various zinc-finger protein partners. Once there, this complex recruits the SETDB1 histone methyltransferase to deposit repressive trimethylation marks at histone H3 lysine 9 (H3K9me3). Already known to be an important mediator of ERE silencing in mouse ESCs, Turelli et al. investigated the role of TRIM28 in human ESCs. They used chromatin immunoprecipitation followed by sequencing (ChIP–seq) to identify TRIM28-binding sites in the genome and also characterized the EREs that become upregulated following TRIM28 knockdown. Overall, they found that TRIM28 is involved in silencing a broad range of ERE types, including human-specific EREs. Through a more global analysis of the transcriptomic and chromatin changes caused by TRIM28 depletion, the authors showed that derepressed EREs can spread activating histone marks into neighbouring genes, thus emphasizing how the occupancy of ERE sequences by TRIM28-containing complexes has effects outside the EREs themselves to regulate cellular genes. Finally, Turelli et al. characterized the complex interplay between DNA methylation and TRIM28-triggered histone methylation for the differential repression of different classes of EREs.
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