Scl specifies hemogenic endothelium and inhibits cardiogenesis via primed enhancers [RNA-seq]

Scl/Tal1 confers hemogenic competence and prevents cardiomyogenesis in embryonic endothelium. Here we show that Scl both directly activates a broad gene regulatory network required for hematopoietic stem/progenitor cell (HS/PC) development, and represses transcriptional regulators required for cardiogenesis. Cardiac repression occurs during a short developmental window through Scl binding to distant cardiac enhancers that harbor H3K4me1 at this stage. Scl binding to hematopoietic regulators extends throughout HS/PC and erythroid development and spreads from distant enhancers to promoters. Surprisingly, Scl complex partners Gata 1 and 2 are dispensable for hematopoietic versus cardiac specification and Scl binding to the majority of its target genes. Nevertheless, Gata factors co-operate with Scl to activate selected transcription factors to facilitate HS/PC emergence from hemogenic endothelium. These results uncover a dual function for Scl in dictating hematopoietic versus cardiac fate choice and suggest a mechanism by which lineage-specific bHLH factors direct the divergence of competing fates.

Scl/Tal1可赋予胚胎内皮细胞生血潜能，并阻断心脏发生过程。本研究证实，Scl既能直接激活造血干/祖细胞（hematopoietic stem/progenitor cell, HS/PC）发育所需的广谱基因调控网络，又能阻遏心脏发生所需的转录调控因子。
心脏命运的阻遏发生于一段短暂的发育窗口期，此时Scl结合该发育阶段带有H3K4me1修饰的远端心脏增强子。Scl与造血调控因子的结合事件贯穿HS/PC及红细胞发育全程，结合范围从远端增强子延伸至基因启动子区域。
令人意外的是，相较于心脏命运特化，Scl的复合体伴侣GATA1与GATA2对于造血命运特化并非必需，且Scl可结合其绝大多数靶基因位点。尽管如此，GATA家族因子可与Scl协同激活特定转录因子，以促进生血内皮细胞向HS/PC的分化产生。
本研究揭示了Scl在调控造血与心脏命运选择中的双重功能，并阐明了谱系特异性碱性螺旋-环-螺旋（basic helix-loop-helix, bHLH）因子如何指导竞争性细胞命运的分化机制。