I focus on the mechanisms that govern transcriptional regulation in normal and disease states, such as cancer. We have identified the transcription factor KAP1/TRIM28 as a major player in global transcriptional regulation, and found that KAP1 is required for recruiting inactive P-TEFb kinase as part of the 7SK complex to promoter-proximal regions of TNF–inducible genes. We have also found that KAP1 and components of the 7SK complex co-occupy promoter-proximal regions of the majority of active Pol II containing genes. We posit that KAP1 positions inactive P-TEFb at promoter-proximal regions of paused genes to allow for rapid kinase activation and transcription elongation.
Using next-generation sequencing methods, I study whether KAP1 regulates expression of the genes that it co-occupies with the 7SK complex, and how KAP1 itself is recruited to chromatin. KAP1 contains a tandem PHD-BRD domain, so KAP1 may recognize specific histone mark(s) to bind chromatin. These studies will help identify how KAP1 regulates its global transcriptional program and show how deregulation of this program leads to disease.