A CpG island-encoded mechanism protects genes from premature transcription termination [SET1_ChIPseq]

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. The genomic distribution of SET1A was profiled in dTAG-SET1A ESCs, in which SET1A can be conditionally depleted. The genomic distribution of H3K4me3 and RNA Pol II was profiled in dTAG-SET1A/B ESCs, in which both SET1A and SET1B can be conditionally depleted. The genomic distribution of ZC3H4 was profiled in untreated ESCs.