Table6_Sin3a associated protein 130 kDa, sap130, plays an evolutionary conserved role in zebrafish heart development.XLSX

Hypoplastic left heart syndrome (HLHS) is a congenital heart disease where the left ventricle is reduced in size. A forward genetic screen in mice identified SIN3A associated protein 130 kDa (Sap130), part of the chromatin modifying SIN3A/HDAC complex, as a gene contributing to the etiology of HLHS. Here, we report the role of zebrafish sap130 genes in heart development. Loss of sap130a, one of two Sap130 orthologs, resulted in smaller ventricle size, a phenotype reminiscent to the hypoplastic left ventricle in mice. While cardiac progenitors were normal during somitogenesis, diminution of the ventricle size suggest the Second Heart Field (SHF) was the source of the defect. To explore the role of sap130a in gene regulation, transcriptome profiling was performed after the heart tube formation to identify candidate pathways and genes responsible for the small ventricle phenotype. Genes involved in cardiac differentiation and cardiac function were dysregulated in sap130a, but not in sap130b mutants. Confocal light sheet analysis measured deficits in cardiac output in MZsap130a supporting the notion that cardiomyocyte maturation was disrupted. Lineage tracing experiments revealed a significant reduction of SHF cells in the ventricle that resulted in increased outflow tract size. These data suggest that sap130a is involved in cardiogenesis via regulating the accretion of SHF cells to the growing ventricle and in their subsequent maturation for cardiac function. Further, genetic studies revealed an interaction between hdac1 and sap130a, in the incidence of small ventricles. These studies highlight the conserved role of Sap130a and Hdac1 in zebrafish cardiogenesis.

心室发育不良综合征（Hypoplastic Left Heart Syndrome, HLHS）是一种左心室体积减少的先天性心脏病。通过小鼠的逆向遗传筛选，确定了SIN3A相关蛋白130kDa（Sap130），该蛋白是染色质修饰的SIN3A/HDAC复合体的一部分，是导致HLHS病因的基因之一。本研究报道了斑马鱼sap130基因在心脏发育中的作用。Sap130同源基因之一sap130a的缺失导致心室体积减小，其表型与小鼠的心室发育不良相似。在节段形成过程中，心脏祖细胞正常，但心室体积的减小提示第二心脏场（Second Heart Field, SHF）是缺陷的来源。为了探讨sap130a在基因调控中的作用，在心管形成后进行了转录组分析，以鉴定与心室小表型相关的候选通路和基因。在sap130a中失调的基因涉及心脏分化和心脏功能，但在sap130b突变体中则没有。共聚焦光片分析测量了MZsap130a心脏输出量的不足，支持了心肌细胞成熟受损的观点。谱系追踪实验揭示了心室中SHF细胞的显著减少，导致流出管大小增加。这些数据表明，sap130a通过调节SHF细胞向生长中的心室的积累以及其随后的成熟来参与心生成。此外，遗传学研究揭示了hdac1与sap130a在心室小发病机制中的相互作用。这些研究突出了Sap130a和Hdac1在斑马鱼心生成中的保守作用。