ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription

  1. Rozenn Riou
  2. Meriem Ladli
  3. Sabine Gerbal-Chaloin
  4. Pascale Bossard
  5. Angélique Gougelet
  6. Cécile Godard
  7. Robin Loesch
  8. Isabelle Lagoutte
  9. Franck Lager
  10. Julien Calderaro
  11. Alexandre Dos Santos
  12. Zhong Wang
  13. Frédérique Verdier
  14. Sabine Colnot  Is a corresponding author
  1. Institut National de la Santé et de la Recherche Médicale, France
  2. Assistance Publique Hôpitaux de Paris, France
  3. University of Michigan, United States

Abstract

Erythropoietin (EPO) is a key regulator of erythropoiesis. The embryonic liver is the main site of erythropoietin synthesis, after which the kidney takes over. The adult liver retains the ability to express EPO, and we discovered here new players of this transcription, distinct from the classical hypoxia-inducible factor pathway. In mice genetically-invalidated in hepatocytes for the chromatin remodeler Arid1a, and for Apc, the major silencer of Wnt pathway, chromatin was more accessible and histone marks turned into active ones at the Epo downstream enhancer. Activating β-catenin signaling increased binding of Tcf4/β-catenin complex and upregulated its enhancer function. The loss of Arid1a together with β-catenin signaling, resulted in cell-autonomous EPO transcription in mouse and human hepatocytes. In mice with Apc-Arid1a gene invalidations in single hepatocytes, Epo de novo synthesis led to its secretion, to splenic erythropoiesis and to dramatic erythrocytosis. Thus, we identified new hepatic EPO regulation mechanism stimulating erythropoiesis.

Data availability

Microarrays have been deposited in GEO database (GSE134553) and are publicly available.All data generated or analysed during this study are included in the manuscript and supporting files. Source data excel files have been provided for Figures 1, 2, 3, 4, 5, 7, 8, 1S1,1S3,3S1,5S1,5S2,7S1.

The following data sets were generated

Article and author information

Author details

  1. Rozenn Riou

    Centre de Recherche des Cordeliers UMRS1138, Institut National de la Santé et de la Recherche Médicale, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Meriem Ladli

    Institut Cochin U1016, Institut National de la Santé et de la Recherche Médicale, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Sabine Gerbal-Chaloin

    IRMB U1183, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Pascale Bossard

    Institut Cochin U1016, Institut National de la Santé et de la Recherche Médicale, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Angélique Gougelet

    Centre de Recherche des Cordeliers UMRS1138, Institut National de la Santé et de la Recherche Médicale, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Cécile Godard

    Centre de Recherche des Cordeliers UMRS1138, Institut National de la Santé et de la Recherche Médicale, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Robin Loesch

    Centre de Recherche des Cordeliers UMRS1138, Institut National de la Santé et de la Recherche Médicale, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Isabelle Lagoutte

    Institut Cochin U1016, Institut National de la Santé et de la Recherche Médicale, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Franck Lager

    Institut Cochin U1016, Institut National de la Santé et de la Recherche Médicale, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Julien Calderaro

    Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Créteil, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Alexandre Dos Santos

    Paul Brousse University Hospital, Institut National de la Santé et de la Recherche Médicale, Villejuif, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Zhong Wang

    Department of Cardiac Surgery, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8720-4609
  13. Frédérique Verdier

    Institut Cochin U1016, Institut National de la Santé et de la Recherche Médicale, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Sabine Colnot

    Centre de Recherche des Cordeliers UMRS1138, Institut National de la Santé et de la Recherche Médicale, Paris, France
    For correspondence
    sabine.colnot@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3949-9107

Funding

Institut National Du Cancer (Epigenetics and Liver Cancer)

  • Rozenn Riou
  • Angélique Gougelet
  • Cécile Godard
  • Julien Calderaro
  • Sabine Colnot

Ligue Contre le Cancer (Equipe Labellisée)

  • Rozenn Riou
  • Angélique Gougelet
  • Cécile Godard
  • Sabine Colnot

Agence Nationale de la Recherche (Labex Who Am I"; Idex "EpilivCan"")

  • Rozenn Riou
  • Angélique Gougelet
  • Cécile Godard
  • Sabine Colnot

Institut National Du Cancer (Chromaliv)

  • Rozenn Riou
  • Angélique Gougelet
  • Cécile Godard
  • Sabine Colnot

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the French government regulations. All of the animals were handled according to approved institutional animal care and use committee (Ethics Committee of Descartes University, Paris). The protocol was approved by the Ethics Committee of Descartes University, Paris (permit number APAFIS#14472). Every effort was made to minimize suffering.

Reviewing Editor

  1. Irwin Davidson, Institut de Génétique et de Biologie Moléculaire et Cellulaire, France

Publication history

  1. Received: November 12, 2019
  2. Accepted: October 20, 2020
  3. Accepted Manuscript published: October 21, 2020 (version 1)
  4. Version of Record published: November 4, 2020 (version 2)

Copyright

© 2020, Riou 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. Rozenn Riou
  2. Meriem Ladli
  3. Sabine Gerbal-Chaloin
  4. Pascale Bossard
  5. Angélique Gougelet
  6. Cécile Godard
  7. Robin Loesch
  8. Isabelle Lagoutte
  9. Franck Lager
  10. Julien Calderaro
  11. Alexandre Dos Santos
  12. Zhong Wang
  13. Frédérique Verdier
  14. Sabine Colnot
(2020)
ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
eLife 9:e53550.
https://doi.org/10.7554/eLife.53550

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