Abstract 18049: Epigenomic Switch by Wnt/β-catenin Signaling Directs Cardiomyocyte Differentiation
Cell fate is determined by extrinsic developmental signals. During this process, transcriptional networks and epigenomic landscapes must be precisely switched. However, how cells integrate extrinsic signals into intrinsic transcriptional networks and re-organize their epigenomes for fate determination remains elusive. During heart development, Wnt/β-catenin signaling regulates mesoderm induction and cardiac mesoderm specification. Here, through integrative analysis of single-cell-transcriptome and epigenome dynamics during cardiomyocyte differentiation, we show that Wnt/β-catenin signaling switches transcriptional networks and epigenomic landscapes by redirecting the pluripotency factor Oct4 (Pou5f1) during cardiac mesoderm specification. Upon differentiation, activation of Wnt signaling induces nuclear accumulation of β-catenin/Brachyury complex, which physically interacts with Oct4 and redirects it from pluripotency enhancers to mesoderm/cardiac mesoderm enhancers. Redirected Oct4 epigenetically activates enhancers by recruiting AT-rich interactive domain-containing protein 1A (Arid1a), which then serves as a platform for the ATP-dependent helicase Brg1 for nucleosome depletion, the methylcytosine dehydrogenases Tet1/Tet2 for DNA demethylation and the histone acetyltransferases p300/CBP for H3K27ac induction. Wnt-induced Oct4 redirection also promotes rapid nucleosome formation at pluripotency enhancers and decommissions the pluripotency gene program, resulting in activation of Oct4/polycomb-repressed cardiac specification genes. Collectively, Wnt signal-induced cardiac mesoderm specification is based on cooperative pioneering binding of β-catenin/Brachyury to enhancer elements for Oct4 redirection, subsequent recruitment of Arid1a-Brg1-Tet1/2-p300/CBP epigenetic activator complex, and Oct4 redirection-induced withdrawal of the pluripotency circuit. We propose that developmental signal-induced regulator-redirection is essential for epigenomic switch in precise conversion of cell fate.
Author Disclosures: S. Nomura: None. T. Fujita: None. A.T. Naito: None. A. Nonaka: None. Y. Kobayashi: None. I. Komuro: None. H. Aburatani: None.
- © 2014 by American Heart Association, Inc.