Targeting CDK12/CYCLIN K induces a gene activation program which is mediated by P-TEFb [Cut&RUN]

Despite major advances, fundamental gaps still remain in understanding how transcriptional programs are dynamically regulated. Gene expression of Human immunodeficiency virus (HIV) is tightly controlled by the cellular transcription machinery, providing a powerful model for studying transcription regulation.

Such gene expression regulation is clinically significant, as HIV persists in long-lived reservoirs even under antiretroviral therapy. Here, we show that selective targeting of CDK12/CYCLIN K (CCNK) induces a global gene activation program, which is mediated by positive transcription elongation factor b (P-TEFb). CDK12/CCNK targeting reshapes promoter-proximal and gene bodies landscape at chromatin, and promotes release of P-TEFb from its inhibitory 7SK snRNP complex.