KAP1 Is a Chromatin Reader that Couples Steps of RNA Polymerase II Transcription to Sustain Oncogenic Programs

Precise control of the RNA polymerase II (Pol II) cycle, including pausing and pause release, maintains transcriptional homeostasis and organismal functions. Much previous work to understand individual transcription steps, but insight into how these steps might be integrated is lacking. Here we reveal a mechanism that integrates Pol II cycle transitions. Surprisingly, the transcription factor KAP1/TRIM28 uses a previously uncharacterized chromatin reader cassette to bind hypo-acetylated histone 4 tails at promoters thereby guaranteeing a continuous progression of Pol II entry to, and exit from, the pause state. Upon chromatin docking, KAP1 first associates with Pol II and then recruits a pathway-specific transcription factor (SMAD2) in response to cognate ligands thereby enabling gene-selective CDK9-dependent pause release. This coupling mechanism is exploited by colorectal cancer cells to aberrantly sustain transcriptional programs commonly dysregulated in cancer patients. The discovery of a factor integrating transcription steps expands the functional repertoire by which chromatin readers operate and provides mechanistic understanding of transcription regulation, offering alternative therapeutic opportunities to target transcriptional dysregulation.