Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment

Wenqing Cai; Sonia Albini; Ke Wei; Erik Willems; Rosa M. Guzzo; Masanao Tsuda; Lorenzo Giordani; Sean Spiering; Leo Kurian; Gene W. Yeo; Pier Lorenzo Puri; Mark Mercola

doi:10.1101/gad.225144.113

Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment

¹Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;
²Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;
³Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92037, USA;
⁴Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00143 Rome, Italy;
⁵Department of Bioengineering, Jacobs School of Engineering, University of California at San Diego, La Jolla, California 92037, USA

↵6 Present address: Department of Orthopaedic Surgery, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.

Abstract

A critical but molecularly uncharacterized step in heart formation and regeneration is the process that commits progenitor cells to differentiate into cardiomyocytes. Here, we show that the endoderm-derived dual Nodal/bone morphogenetic protein (BMP) antagonist Cerberus-1 (Cer1) in embryonic stem cell cultures orchestrates two signaling pathways that direct the SWI/SNF chromatin remodeling complex to cardiomyogenic loci in multipotent (KDR/Flk1⁺) progenitors, activating lineage-specific transcription. Transient inhibition of Nodal by Cer1 induces Brahma-associated factor 60c (Baf60c), one of three Baf60 variants (a, b, and c) that are mutually exclusively assembled into SWI/SNF. Blocking Nodal and BMP also induces lineage-specific transcription factors Gata4 and Tbx5, which interact with Baf60c. siRNA to Cer1, Baf60c, or the catalytic SWI/SNF subunit Brg1 prevented the developmental opening of chromatin surrounding the Nkx2.5 early cardiac enhancer and cardiomyocyte differentiation. Overexpression of Baf60c fully rescued these deficits, positioning Baf60c and SWI/SNF function downstream from Cer1. Thus, antagonism of Nodal and BMP coordinates induction of the myogenic Baf60c variant and interacting transcription factors to program the developmental opening of cardiomyocyte-specific loci in chromatin. This is the first demonstration that cues from the progenitor cell environment direct the subunit variant composition of SWI/SNF to remodel the transcriptional landscape for lineage-specific differentiation.

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Footnotes

↵7 Corresponding author

E-mail mmercola{at}burnham.org
Supplemental material is available for this article.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.225144.113.

Received June 22, 2013.
Accepted October 3, 2013.

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