Differential role of HNF4α isoforms in colitis and colitis-associated colon cancer

Hepatocyte nuclear factor 4alpha (HNF4α) is a nuclear receptor with an emerging role in the gut. While HNF4α has been implicated in colitis and colon cancer in humans, deciphering its functional role is complicated by the existence of two promoters (P1 and P2) in theHNF4A gene that drive the expression of multiple isoforms in the adult intestine. In this study we investigate the roles of P1- and P2-driven HNF4α under conditions of homeostasis, colitis and colitis-associated colon cancer (CAC). P1- and P2-HNF4α are differentially expressed in the differentiated and proliferative compartments of the normal colonic crypt, respectively. Expression profiling of untreated exon swap mice suggests distinct functions of the isoforms that were corroborated in migration and ion transport assays. To investigate the function of the HNF4α isoforms in the colon we utilized HNF4α isoform-specific mice developed previously by an exon swap strategy (PMID: 16498401). WT mice express P1-HNF4α predominantly at the top of the crypt in the differentiated compartment and P2-HNF4α in the bottom, proliferative compartment. The exon swap mice express only P1-HNF4α (α1 HMZ) or P2-HNF4α (α7 HMZ) throughout the colonic crypt. To identify functional differences between the isoforms we performed microarray analysis on RNA isolated from the distal colon of untreated young adult males and found a significant change in a substantial number of genes in the isoform-specific mice compared to their respective WT controls