title: Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer.
abstract: HNF4α has been implicated in colitis and colon cancer in humans but the role of the different HNF4α isoforms expressed from the two different promoters (P1 and P2) active in the colon is not clear. Here, we show that P1-HNF4α is expressed primarily in the differentiated compartment of the mouse colonic crypt and P2-HNF4α in the proliferative compartment. Exon swap mice that express only P1- or only P2-HNF4α 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-HNF4α-only mice (which have elevated levels of the cytokine resistin-like β, RELMβ, and are extremely sensitive to DSS) are crossed with Retnlb(-/-) mice, they are rescued from mortality. Furthermore, P2-HNF4α binds and preferentially activates the RELMβ promoter. In summary, HNF4α isoforms perform non-redundant functions in the colon under conditions of stress, underscoring the importance of tracking them both in colitis and colon cancer.
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, United States.
authors.forename: Karthikeyani
authors.initials: K
authors.lastname: Chellappa
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, United States.
authors.forename: Poonamjot
authors.initials: P
authors.lastname: Deol
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, United States.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Evans
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, United States.
authors.forename: Linh M
authors.initials: LM
authors.lastname: Vuong
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, Riverside, United States.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Nadege
authors.initials: N
authors.lastname: Briançon
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, United States.
authors.forename: Eugene
authors.initials: E
authors.lastname: Bolotin
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, Riverside, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Lytle
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, Riverside, United States.
authors.forename: Meera G
authors.initials: MG
authors.lastname: Nair
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, United States.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Sladek
mesh_terms: D000818:Animals; D003092:Colitis / Q000150:complications / Q000473:pathology*; D003110:Colonic Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D051557:Hepatocyte Nuclear Factor 4 / Q000032:analysis*; D051379:Mice; D020033:Protein Isoforms / Q000032:analysis*
chemical_list: D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D020033:Protein Isoforms
keywords: alternative promoters; cell biology; chromosomes; colitis; colon cancer; colonic crypts; exon swap mice; genes; mouse; nuclear receptor