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

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 <i>Arid1a</i>, and for <i>Apc</i>, the major silencer of Wnt pathway, chromatin was more accessible and histone marks turned into active ones at the <i>Epo</i> downstream enhancer. Activating β-catenin signaling increased binding of Tcf4/β-catenin complex and upregulated its enhancer function. The loss of <i>Arid1a</i> together with β-catenin signaling, resulted in cell-autonomous <i>EPO</i> transcription in mouse and human hepatocytes. In mice with <i>Apc-Arid1a</i> 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 <i>EPO</i> regulation mechanism stimulating erythropoiesis.