title: Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment.
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.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;
authors.forename: Wenqing
authors.initials: W
authors.lastname: Cai
authors.forename: Sonia
authors.initials: S
authors.lastname: Albini
authors.forename: Ke
authors.initials: K
authors.lastname: Wei
authors.forename: Erik
authors.initials: E
authors.lastname: Willems
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Guzzo
authors.forename: Masanao
authors.initials: M
authors.lastname: Tsuda
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Giordani
authors.forename: Sean
authors.initials: S
authors.lastname: Spiering
authors.forename: Leo
authors.initials: L
authors.lastname: Kurian
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
authors.forename: Mark
authors.initials: M
authors.lastname: Mercola
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology*; D004707:Endoderm / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D055457:Nodal Protein / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; C514249:CER1 protein, human; D002868:Chromosomal Proteins, Non-Histone; D016207:Cytokines; C526007:NODAL protein, human; D055457:Nodal Protein; D034741:RNA, Small Interfering; C491649:SMARCD3 protein, human; D014157:Transcription Factors
keywords: Baf60c; Flk1/KDR; Nkx2-5; cardiogenesis; chromatin remodeling; embryonic stem cells