Human TFIIH Kinase CDK7 Regulates Transcription-Associated Epigenetic Modifications

CDK7 phosphorylates the RNA polymerase II (pol II) CTD and activates the P-TEFb-associated kinase, CDK9, but its regulatory roles remain obscure. Here, using human CDK7 analog-sensitive (CDK7as) cells, we observed reduced capping enzyme recruitment, increased pol II promoterproximal pausing, and defective termination at gene 3'-ends upon CDK7 inhibition. Surprisingly, we also noted 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. Mass spectrometry identified factors that bound TFIIH-phosphorylated vs. P-TEFb-phosphorylated CTD (vs. unmodified); capping enzymes and H3K4 methyltransferase complexes, SETD1A/B, selectively bound phosphorylated CTD and the H3K36 methyltransferase SETD2 specifically bound P-TEFb-phosphorylated CTD. Moreover, TFIIH phosphorylated CTD stimulated SETD1A/B activity toward nucleosomes, revealing a mechanistic basis for CDK7 regulation of H3K4me3 spreading. Collectively, these results implicate a CDK7 dependent "CTD code" that regulates epigenetic marks in addition to RNA processing and pol II pausing.