1. Cell Biology
  2. Chromosomes and Gene Expression

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
https://doi.org/10.7554/eLife.10903
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

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.

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.

Metrics

  • 3,177
    views
  • 637
    downloads
  • 66
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Categories and tags

Research organism

Further reading

    1. Cell Biology

    Stratification of enterochromaffin cells by single-cell expression analysis

    Yan Song, Linda J Fothergill ... Gene W Yeo
    Research Article

    Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify 14 EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic, and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.

    1. Cell Biology

    Small-molecule activation of TFEB alleviates Niemann–Pick disease type C via promoting lysosomal exocytosis and biogenesis

    Kaili Du, Hongyu Chen ... Dan Li
    Research Article

    Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

    1. Cell Biology
    2. Developmental Biology

    Lens Development: Bringing signaling complexity into focus

    Sarah Y Coomson, Salil A Lachke
    Insight

    A study in mice reveals key interactions between proteins involved in fibroblast growth factor signaling and how they contribute to distinct stages of eye lens development.