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

  • 3,084
    views
  • 629
    downloads
  • 65
    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
    2. Developmental Biology

    The exocyst complex controls multiple events in the pathway of regulated exocytosis

    Sofía Suárez Freire, Sebastián Perez-Pandolfo ... Mariana Melani
    Research Article

    Eukaryotic cells depend on exocytosis to direct intracellularly synthesized material toward the extracellular space or the plasma membrane, so exocytosis constitutes a basic function for cellular homeostasis and communication between cells. The secretory pathway includes biogenesis of secretory granules (SGs), their maturation and fusion with the plasma membrane (exocytosis), resulting in release of SG content to the extracellular space. The larval salivary gland of Drosophila melanogaster is an excellent model for studying exocytosis. This gland synthesizes mucins that are packaged in SGs that sprout from the trans-Golgi network and then undergo a maturation process that involves homotypic fusion, condensation, and acidification. Finally, mature SGs are directed to the apical domain of the plasma membrane with which they fuse, releasing their content into the gland lumen. The exocyst is a hetero-octameric complex that participates in tethering of vesicles to the plasma membrane during constitutive exocytosis. By precise temperature-dependent gradual activation of the Gal4-UAS expression system, we have induced different levels of silencing of exocyst complex subunits, and identified three temporarily distinctive steps of the regulated exocytic pathway where the exocyst is critically required: SG biogenesis, SG maturation, and SG exocytosis. Our results shed light on previously unidentified functions of the exocyst along the exocytic pathway. We propose that the exocyst acts as a general tethering factor in various steps of this cellular process.

    1. Cancer Biology
    2. Cell Biology

    Automated workflow for the cell cycle analysis of (non-)adherent cells using a machine learning approach

    Kourosh Hayatigolkhatmi, Chiara Soriani ... Simona Rodighiero
    Tools and Resources

    Understanding the cell cycle at the single-cell level is crucial for cellular biology and cancer research. While current methods using fluorescent markers have improved the study of adherent cells, non-adherent cells remain challenging. In this study, we addressed this gap by combining a specialized surface to enhance cell attachment, the FUCCI(CA)2 sensor, an automated image analysis pipeline, and a custom machine learning algorithm. This approach enabled precise measurement of cell cycle phase durations in non-adherent cells. This method was validated in acute myeloid leukemia cell lines NB4 and Kasumi-1, which have unique cell cycle characteristics, and we tested the impact of cell cycle-modulating drugs on NB4 cells. Our cell cycle analysis system, which is also compatible with adherent cells, is fully automated and freely available, providing detailed insights from hundreds of cells under various conditions. This report presents a valuable tool for advancing cancer research and drug development by enabling comprehensive, automated cell cycle analysis in both adherent and non-adherent cells.

    1. Cell Biology

    Spatiotemporal recruitment of the ubiquitin-specific protease USP8 directs endosome maturation

    Yue Miao, Yongtao Du ... Mei Ding
    Research Article

    The spatiotemporal transition of small GTPase Rab5 to Rab7 is crucial for early-to-late endosome maturation, yet the precise mechanism governing Rab5-to-Rab7 switching remains elusive. USP8, a ubiquitin-specific protease, plays a prominent role in the endosomal sorting of a wide range of transmembrane receptors and is a promising target in cancer therapy. Here, we identified that USP8 is recruited to Rab5-positive carriers by Rabex5, a guanine nucleotide exchange factor (GEF) for Rab5. The recruitment of USP8 dissociates Rabex5 from early endosomes (EEs) and meanwhile promotes the recruitment of the Rab7 GEF SAND-1/Mon1. In USP8-deficient cells, the level of active Rab5 is increased, while the Rab7 signal is decreased. As a result, enlarged EEs with abundant intraluminal vesicles accumulate and digestive lysosomes are rudimentary. Together, our results reveal an important and unexpected role of a deubiquitinating enzyme in endosome maturation.