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.

DOI: http://dx.doi.org/10.7554/eLife.10903.001

eLife digest

The digestive system in animals consists of a network of organs – including the liver, stomach, pancreas and intestines – that work together to break down food and deliver energy to the rest of the body. Many proteins called transcription factors help to guide the development of these organs and keep them healthy throughout life. Among these is a protein called HNF4α. In various diseases of the digestive system, such as gastric cancer or inflammatory bowel disease, the production of HNF4α is not properly regulated.

Gene expression can be activated by transcription factors binding to regions of DNA called promoters. The gene that encodes HNF4α has two promoters called P1 and P2, and each produce several different versions of the HNF4α protein.

The colon contains intestinal glands (also known as colonic crypts) that contain a lower part in which cells actively divide and an upper part of non-dividing cells that help with digestion. Previous studies have shown that if the mouse colon is unable to produce HNF4α, the structure of the crypts is disrupted. By studying crypts taken from the colon of mice, Chellappa et al. have now found that P1-HNF4α proteins are mainly produced at the top of the crypts, whereas P2-HNF4α proteins are found mainly at the bottom.

Chellappa et al. then used two sets of genetically engineered mice: one that can only produce P1-HNFα proteins, and one that only has P2-HNFα proteins. Under normal conditions both sets of mice appeared healthy. However, differences became apparent if the mice were subjected to treatments that cause colitis or colitis-associated colon cancer. Mice that could only produce P1-HNF4α proteins were less susceptible to colitis and got fewer and smaller tumors than normal mice. By contrast, mice that could only produce P2-HNF4α experienced more colitis and developed more tumors than normal mice.

Comparing the genes expressed in the colon cells of these two types of mice revealed several differences. In particular, much more of a pro-inflammatory protein called RELMβ was produced in P2-only mice. Chellappa et al. then proceeded to show that RELMβ is essential for the susceptibility of P2-mice to coliltis.

Overall, the experiments show that P1-HNF4α and P2-HNF4α perform different tasks both in the healthy and the diseased mouse colon. In future it will be important to work out how the balance between the two sets of proteins is disrupted in diseases of the colon.

DOI: http://dx.doi.org/10.7554/eLife.10903.002