Steven O’Hara, PhD

PSC Research Fund Pilot Research Award
$50,000 over one year

Mayo Clinic

Bromodomain and extraterminal domain (BET) protein function in PSC

We have identified in livers from patients with PSC, that -40% of the cholangiocytes (epithelial cells that line bile ducts) become senescent (can no longer undergo cell division) and drive fibrosis and inflammation. We have also demonstrated that the characteristics of senescent cholangiocytes (cell cycle withdrawal, cell death resistance, and a proinflammatory secretome) are regulated by epigenetic modification of senescence-associated genomic regions.

Epigenetic modification refers to chemical modifications to DNA or DNA-associated histone proteins, rendering regions of the genome compacted and silenced or open and accessible for gene expression. The proteins that modify and interpret the epigenome can be broadly categorized as epigenetic writers, erasers, and readers. A prominent family of epigenetic readers, the bromodomain and extra-terminal domain (BET) proteins, are central mediators of transcription and are implicated in the regulation of cell growth, differentiation, and inflammation. Drugs that inhibit BET proteins have already shown efficacy in certain cancers, and inflammatory diseases, and are currently in clinical trials; however, there are no active trials for BET protein inhibitors for PSC. In work we recently published (GASTROENTEROLOGY, 2023), we demonstrated that: i) senescent cholangiocytes from PSC patients and PSC animal models overexpress two BET proteins, BRD2 and BRD4; ii) BET protein inhibitors reduce senescence and the inflammatory secretome in both cultured normal human cholangiocytes (NHC) experimentally induced to senescence and in cholangiocytes derived from patients with PSC; and, iii) BET protein inhibitors reduced fibrosis, inflammation, and senescence in two mouse models of PSC. Our data support the notion that BET proteins play an essential role in maintaining the cholangiocyte senescence-associated inflammatory secretome; however, the mechanisms driving this phenotype remain obscure and are the focus of this application.