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Baf60c is essential for function of BAF chromatin remodelling complexes in heart development

机译：Baf60c对于心脏发育中BAF染色质重塑复合物的功能至关重要

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摘要

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.
机译：组织特异性转录因子调节胚胎发育的几个重要方面。它们必须在组装成染色质高阶结构的DNA中起作用。诸如Swi / Snf样BAF复合物之类的酶复合物可重塑染色质，以使转录机制可访问基因调控元件（1,2）。在这里，我们显示了编码Baf60c（BAF复合体的一个亚基）的Smarcd3在心脏中表达，并在早期小鼠胚胎的体节中表达。 RNA干扰使Smarcd3在源自胚胎干细胞的小鼠胚胎中沉默，导致心脏形态发生缺陷，反映了前/次心脏场的扩张受损，还导致异常的心脏和骨骼肌分化。 Smarcd3表达的中间降低会导致流出道重塑缺陷，让人联想到人类先天性心脏缺陷。在细胞培养物中过表达的Baf60c可以介导心脏转录因子与BAF复合物ATPase Brg1之间的相互作用，从而增强靶基因的激活。这些结果揭示了Baf60c在将BAF染色质重塑复合物募集到心脏特异性增强子方面的组织特异性和剂量依赖性作用，提供了确保器官发生过程中转录调控的新机制。

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