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

Karthikeyani Chellappa,Jane R Evans,Linh M Vuong,Nadege Briançon,Christian Lytle,Eugene Bolotin,Frances M Sladek,Gang Chen,Meera G Nair,Poonamjot Deol

doi:10.7554/elife.10903

Karthikeyani Chellappa, Jane R Evans + Show 8 more

Open Access

https://doi.org/10.7554/elife.10903

Copy DOI

Journal: eLife	Publication Date: May 11, 2016
Citations: 67	License type: CC BY 4.0

Affiliation: University of California, Riverside

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.

Highlights

Hepatocyte nuclear factor 4alpha (HNF4a) (NR2A1) is a highly conserved member of nuclear receptor superfamily of ligand-dependent transcription factors that is expressed in liver, kidney, pancreas, stomach and intestine (Sladek et al, 1990)
We recently showed that ectopic expression of P1- but not P2-HNF4a decreased the tumorigenic potential of the human colon cancer cell line HCT116 in a mouse xenograft model (Vuong et al, 2015), suggesting that the different HNF4a isoforms may play distinct roles in the colon
While there was some expression of P2-HNF4a in the differentiated compartment, it was notably absent from the surface epithelium (Figure 1B)

Summary

Introduction

Hepatocyte nuclear factor 4alpha (HNF4a) (NR2A1) is a highly conserved member of nuclear receptor superfamily of ligand-dependent transcription factors that is expressed in liver, kidney, pancreas, stomach and intestine (Sladek et al, 1990). HNF4a is best known for its role in the liver where it is a master regulator of liver-specific gene expression and essential for adult and fetal liver function (Hayhurst et al, 2001; Kaestner, 2010; Bolotin et al, 2010; Odom, 2004). Knockout of the Hnf4a gene in the embryonic mouse colon results in disrupted crypt topology, and a decreased number of epithelial and mature goblet cells (Garrison et al, 2006), while the adult intestinal knockout shows defects in the balance between proliferation and differentiation as well as immune function, ion transport, epithelial barrier function and oxidative stress (Ahn et al, 2008; Cattin et al, 2009; Darsigny et al, 2009; 2010; Chahar et al, 2014). Dysregulation of the HNF4A gene is linked to several gastrointestinal disorders including colitis and colon cancer and a single nucleotide polymorphism in the HNF4A gene region is associated with ulcerative colitis (Ahn et al, 2008; Chellappa et al, 2012; Tanaka et al, 2006; Oshima et al, 2007; Barrett et al, 2009)

Methods

Results

Conclusion