Human TFIIH kinase CDK7 regulates transcription-associated epigenetic modification

CDK7 phosphorylates the RNA polymerase II (pol II) CTD and activates the P-TEFb- associated kinase, CDK9, but its regulatory roles remain obscure. Using human CDK7 analog-sensitive (CDK7as) cells, we observed reduced capping enzyme recruitment, increased pol II promoter-proximal pausing, and defective termination at gene 3'-ends upon CDK7 inhibition. We also found that CDK7 regulates chromatin modifications downstream of transcription start sites. H3K4me3 spreading was restricted at gene 5'-ends and H3K36me3 was displaced toward gene 3'-ends in CDK7as cells. Together, these results implicate a CDK7-dependent "CTD code" that regulates epigenetic marks in addition to RNA processing and pol II pausing. WT and analogue sensitive Cdk7as mutant cells were treated with the ATP analogue NM-PP1 that specifically inhibits the Cdk7as mutant kinase. Using ChIP-seq and RNA-seq we tested the effects of Cdk7 inactivation on pol II distribution along genes, CTD Ser2 and Ser5 phosphorylation, capping enzyme recruitment, histone H3K4 and H3K36 methylation and mRNA expression