A CpG island-encoded mechanism protects genes from premature transcription termination

Abstract

Transcription must be highly controlled to regulate gene expression and development. However, our understanding of the molecular mechanisms that influence transcription and how these are coordinated in cells to ensure normal gene expression remains rudimentary. Here, we reveal that actively transcribed CpG island-associated gene promoters recruit SET1 chromatin modifying complexes to enable gene expression. Counterintuitively, this effect is independent of SET1 complex histone modifying activity, and instead relies on the capacity of these complexes to interact with the RNA Polymerase II-binding protein, WDR82. Unexpectedly, we discover that SET1 complexes sustain gene transcription by counteracting the activity of the ZC3H4/WDR82 protein complex, which we show can pervasively terminate both genic and extragenic transcription. Therefore, we discover a new gene regulatory mechanism whereby CpG island elements nucleate a protein complex that protects genic transcription from premature termination, effectively distinguishing genic from non-genic transcription to enable gene expression.

Transcriptome-wide analysis of primary human endothelial cell responses to 1 hour of protein translation inhibition identify nonsense mediated decay targets and a non-codingSLC11A2exon as an acute biomarker

“…Identification of the integrator complex is highly relevant to recent data indicating that the integrator complex regulates production of full length coding and non-coding RNAs by mechanisms including RNA cleavage, [53] RNA polymerase II pausing, [54] premature transcriptional termination, [55] and RISC loading of miRNAs. [56] ATP is relevant particularly to UPF1 which has both ATPase and RNA helicase activities.…”