Sin3a associated protein 130 kDa, sap130, plays an evolutionary conserved role in zebrafish heart development.
Sin3a associated protein 130 kDa, sap130, plays an evolutionary conserved role in zebrafish heart development.
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DOI：
10.3389/fcell.2023.1197109
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发表时间：
2023
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
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左心发育不良综合征（HLHS）是一种左心室缩小的先天性心脏病。在小鼠中进行的正向遗传筛选鉴定了SIN 3A相关蛋白130 kDa（Sap 130），染色质修饰SIN 3A/HDAC复合物的一部分，作为导致HLHS病因的基因。在这里，我们报告斑马鱼sap 130基因在心脏发育中的作用。sap 130 a是两个sap 130同源基因之一，缺失sap 130 a导致心室尺寸变小，这是一种让人联想到小鼠左心室发育不良的表型。虽然心脏祖细胞在体节发生过程中是正常的，但心室大小的减小表明第二心脏野（SHF）是缺陷的来源。为了探索sap 130 a在基因调控中的作用，在心管形成后进行转录组分析以鉴定负责小心室表型的候选途径和基因。心脏分化和心脏功能相关基因在sap 130 a突变体中表达异常，但在sap 130 b突变体中没有。共聚焦光片分析测量了MZsap 130 a中心输出量的不足，支持心肌细胞成熟被破坏的观点。谱系追踪实验显示，心室中SHF细胞显著减少，导致流出道尺寸增加。这些数据表明，sap 130 a是通过调节SHF细胞的增长，以不断增长的心室，并在其随后的心脏功能的成熟参与心脏发生。此外，遗传研究揭示了hdac 1和sap 130 a之间的相互作用，在小心室的发病率。这些研究强调了Sap 130 a和Hdac 1在斑马鱼心脏发生中的保守作用。
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.
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影响因子：
--
作者：
Girstmair J;Zakrzewski A;Lapraz F;Handberg-Thorsager M;Tomancak P;Pitrone PG;Simpson F;Telford MJ
通讯作者：
Telford MJ
影响因子：
20.1
作者：
Fahed AC;Gelb BD;Seidman JG;Seidman CE
通讯作者：
Seidman CE
低塑性左心综合征。
影响因子：
3.7
作者：
通讯作者：
--
影响因子：
3.8
作者：
Grimes, Adrian C.;Erwin, Kyle N.;Kirby, Margaret L.
通讯作者：
Kirby, Margaret L.
影响因子：
5.4
作者：
Gabriel GC;Devine W;Redel BK;Whitworth KM;Samuel M;Spate LD;Cecil RF;Prather RS;Wu Y;Wells KD;Lo CW
通讯作者：
Lo CW