Uncovering new regulatory mechanisms of acetylation-dependent enhancer-promoter communication.

Transcriptional gene regulatory networks are composed of trans-acting factors encoded by the genome which can bind cis-regulatory DNA sequence elements to modulate transcription of target genes and determine cell state throughout development, homeostasis, and disease. The human genome is predicted to encode ~1,600 transcription factors and 3,500,000 cis-regulatory elements, with over 1,000,000 of these cis-regulatory elements predicted to be enhancers. Enhancers were first discovered and functionally defined in 1981 when a 72bp tandem sequence from the SV40 genome was found to strongly induce transcription in cis from large distances, independent of its orientation relative to transcriptional promoters. The DNA sequence logic underlying enhancer function is still poorly understood, as highly divergent sequences can generate functionally indistinguishable outputs. However, a set of biochemical and architectural features has become associated with regions demonstrating enhancer activity. One of these features is binding of a histone acetyltransferase called P300.  I propose to leverage a combination of genetic and biochemical approaches to gain insight into the molecular mechanisms of P300-dependent enhancer-promoter communication.