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

• Main Authors: Rozenn Riou, Meriem Ladli, Sabine Gerbal-Chaloin, Pascale Bossard, Angélique Gougelet, Cécile Godard, Robin Loesch, Isabelle Lagoutte, Franck Lager, Julien Calderaro, Alexandre Dos Santos, Zhong Wang, Frédérique Verdier, Sabine Colnot
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2020-10-01
• Series: eLife
• Subjects: chromatin remodeling; Wnt signaling; epo transcription; liver physiopathology
• Online Access: https://elifesciences.org/articles/53550

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.