title: Selective and reversible suppression of intestinal stem cell differentiation by pharmacological inhibition of BET bromodomains.
abstract: Absorptive and secretory cells of the small intestine are derived from a single population of Lgr5-expressing stem cells. While key genetic pathways required for differentiation into specific lineages have been defined, epigenetic programs contributing to this process remain poorly characterized. Members of the BET family of chromatin adaptors contain tandem bromodomains that mediate binding to acetylated lysines on target proteins to regulate gene expression. In this study, we demonstrate that mice treated with a small molecule inhibitor of BET bromodomains, CPI203, exhibit greater than 90% decrease in tuft and enteroendocrine cells in both crypts and villi of the small intestine, with no changes observed in goblet or Paneth cells. BET bromodomain inhibition did not alter the abundance of Lgr5-expressing stem cells in crypts, but rather exerted its effects on intermediate progenitors, in part through regulation of Ngn3 expression. When BET bromodomain inhibition was combined with the chemotherapeutic gemcitabine, pervasive apoptosis was observed in intestinal crypts, revealing an important role for BET bromodomain activity in intestinal homeostasis. Pharmacological targeting of BET bromodomains defines a novel pathway required for tuft and enteroendocrine differentiation and provides an important tool to further dissect the progression from stem cell to terminally differentiated secretory cell.
authors: Department of Surgery and The Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston MA, USA.
authors: Akifumi
authors: A
authors: Nakagawa
authors: Department of Surgery and The Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston MA, USA.
authors: Curtis E
authors: CE
authors: Adams
authors: Department of Surgery and The Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston MA, USA.
authors: Yinshi
authors: Y
authors: Huang
authors: Department of Surgery and The Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston MA, USA.
authors: Sulaiman R
authors: SR
authors: Hamarneh
authors: Department of Surgery and The Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston MA, USA.
authors: Wei
authors: W
authors: Liu
authors: Department of Surgery and The Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston MA, USA.
authors: Kate N
authors: KN
authors: Von Alt
authors: Department of Pathology, Massachusetts General Hospital, Boston MA, USA.
authors: Mari
authors: M
authors: Mino-Kenudson
authors: Department of Surgery and The Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston MA, USA.
authors: Richard A
authors: RA
authors: Hodin
authors: Department of Surgery and The Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston MA, USA.
authors: Keith D
authors: KD
authors: Lillemoe
authors: Department of Surgery and The Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston MA, USA.
authors: Carlos
authors: C
authors: Fernández-Del Castillo
authors: Department of Surgery and The Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston MA, USA.
authors: Andrew L
authors: AL
authors: Warshaw
authors: Department of Surgery and The Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston MA, USA.
authors: Andrew S
authors: AS
authors: Liss
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D019858:Enteroendocrine Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis
chemical_list: D000081:Acetamides; D001381:Azepines; C000599185:CPI203; C493597:Lgr5 protein, mouse; D009687:Nuclear Proteins; D043562:Receptors, G-Protein-Coupled