Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment.
Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment.
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DOI：
10.1101/gad.225144.113
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发表时间：
2013-11-01
影响因子：
10.5
通讯作者：
Mercola M
中科院分区：
文献类型：
--
作者：
Cai W;Albini S;Wei K;Willems E;Guzzo RM;Tsuda M;Giordani L;Spiering S;Kurian L;Yeo GW;Puri PL;Mercola M
心脏的形成和再生需要心肌细胞的参与。Cai等人的研究表明，双结/BMP拮抗剂Cerberus-1 （Cer1）将SWI/SNF染色质重塑复合体引导到多能祖细胞的心肌形成位点。阻断Nodal和BMP诱导Baf60c和与Baf60c相互作用的谱系特异性转录因子。敲低Cer1、Baf60c或催化SWI/SNF亚基Brg1可阻止心肌细胞分化。这些结果证明了来自祖细胞环境的外部信号如何指导谱系特异性染色质重塑以决定细胞命运。在心脏形成和再生过程中，一个关键但分子上未被表征的步骤是使祖细胞分化为心肌细胞的过程。在这里，我们发现胚胎干细胞培养中的内胚层来源的双结/骨形态发生蛋白（BMP）拮抗剂Cerberus-1 （Cer1）协调了两条信号通路，将SWI/SNF染色质重塑复合体引导到多能（KDR/Flk1+）祖细胞的心肌形成位点，激活谱系特异性转录。Cer1对Nodal的短暂抑制诱导Brahma-associated factor 60c (Baf60c)， Baf60c是三种Baf60变体（a、b和c）中的一种，它们相互排斥地组装成SWI/SNF。阻断Nodal和BMP还可诱导与Baf60c相互作用的谱系特异性转录因子Gata4和Tbx5。siRNA与Cer1、Baf60c或催化SWI/SNF亚基Brg1的结合阻止了Nkx2.5早期心脏增强子周围染色质的发育打开和心肌细胞分化。Baf60c的过表达完全挽救了这些缺陷，将Baf60c和SWI/SNF功能定位在Cer1的下游。因此，Nodal和BMP的拮抗协调了肌源性Baf60c变异的诱导和相互作用的转录因子，以编程染色质中心肌细胞特异性位点的发育开放。这是首次证明来自祖细胞环境的线索指导SWI/SNF的亚基变异组成，以重塑谱系特异性分化的转录景观。
Heart formation and regeneration require cardiomyocyte commitment. Cai et al. show that the dual Nodal/BMP antagonist Cerberus-1 (Cer1) directs the SWI/SNF chromatin remodeling complex to cardiomyogenic loci in multipotent progenitors. Blocking Nodal and BMP induces Baf60c and lineage-specific transcription factors that interact with Baf60c. Knockdown of Cer1, Baf60c, or the catalytic SWI/SNF subunit Brg1 prevented cardiomyocyte differentiation. These results demonstrate how external signals from the progenitor cell environment can direct lineage-specific chromatin remodeling in order to commit cell fate. 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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DOI：
10.1073/pnas.1016959108
发表时间：
2011-04-05
影响因子：
11.1
作者：
He, Aibin;Kong, Sek Won;Pu, William T.
通讯作者：
Pu, William T.
影响因子：
23.9
作者：
Morrison, Gillian M.;Oikonomopoulou, Ifigenia;Brickman, Joshua M.
通讯作者：
Brickman, Joshua M.
影响因子：
64.8
作者：
Brennan, J;Lu, CC;Robertson, EJ
通讯作者：
Robertson, EJ
DOI：
10.1073/pnas.0704044104
发表时间：
2007-06-26
影响因子：
11.1
作者：
Kwon, Chulan;Arnold, Joshua;Srivastava, Deepak
通讯作者：
Srivastava, Deepak
DOI：
10.1073/pnas.0605768103
发表时间：
2006-12-26
影响因子：
11.1
作者：
Naito, Atsuhiko T.;Shiojima, Ichiro;Komuro, Issei
通讯作者：
Komuro, Issei