ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
- Institut National de la Santé et de la Recherche Médicale, France
- Assistance Publique Hôpitaux de Paris, France
- 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.
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Expression data from isolated areas from [Apc-Arid1a]ko-focal liver tissues after FFPE treatmentNCBI Gene Expression Omnibus, GSE134553.
Article and author information
Author details
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.
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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ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
eLife 9:e53550.
https://doi.org/10.7554/eLife.53550
Further reading
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Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.
