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

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 hy...

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Autores principales: Riou, Rozenn, Ladli, Meriem, Gerbal-Chaloin, Sabine, Bossard, Pascale, Gougelet, Angélique, Godard, Cécile, Loesch, Robin, Lagoutte, Isabelle, Lager, Franck, Calderaro, Julien, Dos Santos, Alexandre, Wang, Zhong, Verdier, Frédérique, Colnot, Sabine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641585/
https://www.ncbi.nlm.nih.gov/pubmed/33084574
http://dx.doi.org/10.7554/eLife.53550
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author Riou, Rozenn
Ladli, Meriem
Gerbal-Chaloin, Sabine
Bossard, Pascale
Gougelet, Angélique
Godard, Cécile
Loesch, Robin
Lagoutte, Isabelle
Lager, Franck
Calderaro, Julien
Dos Santos, Alexandre
Wang, Zhong
Verdier, Frédérique
Colnot, Sabine
author_facet Riou, Rozenn
Ladli, Meriem
Gerbal-Chaloin, Sabine
Bossard, Pascale
Gougelet, Angélique
Godard, Cécile
Loesch, Robin
Lagoutte, Isabelle
Lager, Franck
Calderaro, Julien
Dos Santos, Alexandre
Wang, Zhong
Verdier, Frédérique
Colnot, Sabine
author_sort Riou, Rozenn
collection PubMed
description 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.
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spelling pubmed-76415852020-11-05 ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription Riou, Rozenn Ladli, Meriem Gerbal-Chaloin, Sabine Bossard, Pascale Gougelet, Angélique Godard, Cécile Loesch, Robin Lagoutte, Isabelle Lager, Franck Calderaro, Julien Dos Santos, Alexandre Wang, Zhong Verdier, Frédérique Colnot, Sabine eLife Chromosomes and Gene Expression 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. eLife Sciences Publications, Ltd 2020-10-21 /pmc/articles/PMC7641585/ /pubmed/33084574 http://dx.doi.org/10.7554/eLife.53550 Text en © 2020, Riou et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Chromosomes and Gene Expression
Riou, Rozenn
Ladli, Meriem
Gerbal-Chaloin, Sabine
Bossard, Pascale
Gougelet, Angélique
Godard, Cécile
Loesch, Robin
Lagoutte, Isabelle
Lager, Franck
Calderaro, Julien
Dos Santos, Alexandre
Wang, Zhong
Verdier, Frédérique
Colnot, Sabine
ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
title ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
title_full ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
title_fullStr ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
title_full_unstemmed ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
title_short ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
title_sort arid1a loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
topic Chromosomes and Gene Expression
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641585/
https://www.ncbi.nlm.nih.gov/pubmed/33084574
http://dx.doi.org/10.7554/eLife.53550
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