Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer

HNF4 alpha has been implicated in colitis and colon cancer in humans but the role of the different HNF4 alpha isoforms expressed from the two different promoters (P1 and P2) active in the colon is not clear. Here, we show that P1-HNF4 alpha is expressed primarily in the differentiated compartment of the mouse colonic crypt and P2-HNF4 alpha in the proliferative compartment. Exon swap mice that express only P1- or only P2-HNF4 alpha 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 alpha-only mice (which have elevated levels of the cytokine resistin-like b, RELMb, and are extremely sensitive to DSS) are crossed with Retnlb(-/-) mice, they are rescued from mortality. Furthermore, P2-HNF4 alpha binds and preferentially activates the RELMb promoter. In summary, HNF4 alpha isoforms perform non-redundant functions in the colon under conditions of stress, underscoring the importance of tracking them both in colitis and colon cancer.