Genomic DNA is a shared substrate for the two principal processes in the cell nucleus – gene transcription and DNA replication. My lab aims to understand what aspects of the regulation of these processes differentiate healthy and diseased cells. Ultimately, we hope to reveal specific dependencies, paving the way for the development of new targeted therapies. Conservation of factors and pathways involved in transcription and DNA replication allows us to use the powerful yeast system as our primary model.

We previously characterized yeast bromodomain-containing factors Bdf1/2 as functional homologues of chromatin readers from the human BET family. Aberrant activity of human BET proteins in transcriptional regulation has been linked with the development and progression of many diseases. Canonical models assert that, as chromatin readers, BET proteins are recruited to regulatory elements by their tandem bromodomains, which ‘read’ acetylated chromatin. However, it is less clear how BET proteins regulate transcription once recruited, and recent evidence suggests that bromodomain activity alone does not fully explain recruitment. For example, diseased cells quickly develop resistance to therapeutics that specifically inhibit bromodomain activity.

Further complicating the subject, our recent unpublished findings have implicated BET proteins in the regulation of DNA replication. Based on this background, we are now exploring the roles of BET proteins in both transcription and DNA replication.

The maintenance of cellular homeostasis and genome stability depends on the strict control of gene transcription and DNA replication, and the spatiotemporal coordination of the two processes to avoid conflicts. A plausible model asserts that transcription and DNA replication are coordinated at the early stages when respective machineries are assembled and activated.

Based on this background and our unpublished findings, we are testing a model where BET proteins function as a direct link between genome-wide regulation of transcription and DNA replication. Our preliminary data indicate that BET proteins may facilitate the crosstalk between transcription and DNA replication at least partially through the recruitment of distinct protein complexes involved in chromatin dynamics. We are also testing if replication initiation factors directly contribute to the regulation of transcription when cells prepare for DNA replication.