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

  1. Karthikeyani Chellappa
  2. Poonamjot Deol
  3. Jane R Evans
  4. Linh M Vuong
  5. Gang Chen
  6. Nadege Briançon
  7. Eugene Bolotin
  8. Christian Lytle
  9. Meera G Nair
  10. Frances M Sladek  Is a corresponding author
  1. University of Pennsylvania, United States
  2. University of California, Riverside, United States
  3. Harvard Medical School, United States
  4. University of California Riverside, United States

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.

Article and author information

Author details

  1. Karthikeyani Chellappa

    Institute for Diabetes, Obesity, and Metabolism, Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Poonamjot Deol

    Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jane R Evans

    Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Linh M Vuong

    Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Gang Chen

    Division of Biomedical Sciences, University of California, Riverside, Riverside, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nadege Briançon

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Eugene Bolotin

    Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Christian Lytle

    Division of Biomedical Sciences, University of California, Riverside, Riverside, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Meera G Nair

    Division of Biomedical Sciences, University of California, Riverside, Riverside, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Frances M Sladek

    Department of Cell Biology and Neuroscience, University of California Riverside, Riverside, United States
    For correspondence
    frances.sladek@ucr.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Kevin Struhl, Harvard Medical School, United States

Ethics

Animal experimentation: Care and treatment of animals were in strict accordance with guidelines from the University of California Riverside Institutional Animal Care and Use Committee. Institutional protocol number A200140014.

Version history

  1. Received: August 15, 2015
  2. Accepted: May 9, 2016
  3. Accepted Manuscript published: May 11, 2016 (version 1)
  4. Accepted Manuscript updated: May 14, 2016 (version 2)
  5. Version of Record published: June 14, 2016 (version 3)

Copyright

© 2016, Chellappa et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Karthikeyani Chellappa
  2. Poonamjot Deol
  3. Jane R Evans
  4. Linh M Vuong
  5. Gang Chen
  6. Nadege Briançon
  7. Eugene Bolotin
  8. Christian Lytle
  9. Meera G Nair
  10. Frances M Sladek
(2016)
Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer
eLife 5:e10903.
https://doi.org/10.7554/eLife.10903

Share this article

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

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