Baf60c is essential for function of BAF chromatin remodelling complexes in heart development
Baf60c is essential for function of BAF chromatin remodelling complexes in heart development
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DOI：
10.1038/nature03071
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发表时间：
2004-11-04
期刊：
影响因子：
64.8
通讯作者：
Bruneau, BG
中科院分区：
文献类型：
--
作者：
Lickert, H;Takeuchi, JK;Bruneau, BG
组织特异性转录因子调节胚胎发育的几个重要方面。它们必须在DNA组装成染色质的高级结构的背景下发挥作用。酶复合物如Swi/Snf样BAF复合物重塑染色质，使转录机制接近基因调控元件（1，2）。在这里，我们表明，Smarcd 3，编码Baf 60 c，BAF复合物的亚基，在早期小鼠胚胎的心脏和体节中特异性表达。在来自胚胎干细胞的小鼠胚胎中，通过RNA干扰进行Smarcd 3沉默导致心脏形态发生缺陷，这反映了前/次级心脏领域的扩张受损，并且还导致异常的心脏和骨骼肌分化。Smarcd 3表达的中间减少导致流出道重塑缺陷，使人联想到人类先天性心脏缺陷。在细胞培养物中过表达的Baf 60 c可以介导心脏转录因子与BAF复合物ATP酶Brg 1之间的相互作用，从而增强靶基因的激活。这些结果揭示了Baf 60 c在招募BAF染色质重塑复合物到心脏特异性增强子中的组织特异性和剂量依赖性作用，提供了一种新的机制来确保器官发生过程中的转录调控。
Tissue-specific transcription factors regulate several important aspects of embryonic development. They must function in the context of DNA assembled into the higher-order structure of chromatin. Enzymatic complexes such as the Swi/Snf-like BAF complexes remodel chromatin to allow the transcriptional machinery access to gene regulatory elements(1,2). Here we show that Smarcd3, encoding Baf60c, a subunit of the BAF complexes, is expressed specifically in the heart and somites in the early mouse embryo. Smarcd3 silencing by RNA interference in mouse embryos derived from embryonic stem cells causes defects in heart morphogenesis that reflect impaired expansion of the anterior/secondary heart field, and also results in abnormal cardiac and skeletal muscle differentiation. An intermediate reduction in Smarcd3 expression leads to defects in outflow tract remodelling reminiscent of human congenital heart defects. Baf60c overexpressed in cell culture can mediate interactions between cardiac transcription factors and the BAF complex ATPase Brg1, thereby potentiating the activation of target genes. These results reveal tissue-specific and dose-dependent roles for Baf60c in recruiting BAF chromatin remodelling complexes to heart-specific enhancers, providing a novel mechanism to ensure transcriptional regulation during organogenesis.