Opposing roles of nuclear receptor HNF4? isoforms in colitis and colitis-associated colon cancer.

ABSTRACT: HNF4? has been implicated in colitis and colon cancer in humans but the role of the different HNF4? isoforms expressed from the two different promoters (P1 and P2) active in the colon is not clear. Here, we show that P1-HNF4? is expressed primarily in the differentiated compartment of the mouse colonic crypt and P2-HNF4? in the proliferative compartment. Exon swap mice that express only P1- or only P2-HNF4? have different colonic gene expression profiles, interacting proteins, cellular migration, ion transport and epithelial barrier function. The mice also exhibit altered susceptibilities to experimental colitis (DSS) and colitis-associated colon cancer (AOM+DSS). When P2-HNF4?-only mice (which have elevated levels of the cytokine resistin-like ?, RELM?, and are extremely sensitive to DSS) are crossed with Retnlb(-/-) mice, they are rescued from mortality. Furthermore, P2-HNF4? binds and preferentially activates the RELM? promoter. In summary, HNF4? isoforms perform non-redundant functions in the colon under conditions of stress, underscoring the importance of tracking them both in colitis and colon cancer.

SUBMITTER: Chellappa K 

PROVIDER: S-EPMC4907689 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature