HIRA Is Required for Heart Development and Directly Regulates Tnni2 and Tnnt3.
HIRA Is Required for Heart Development and Directly Regulates Tnni2 and Tnnt3.
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DOI：
10.1371/journal.pone.0161096
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Chapgier AL
中科院分区：
文献类型：
--
作者：
Dilg D;Saleh RN;Phelps SE;Rose Y;Dupays L;Murphy C;Mohun T;Anderson RH;Scambler PJ;Chapgier AL
染色质重塑对心脏发育至关重要。有趣的是，组蛋白伴侣在这方面的作用尚未研究。HIRA是HUCA（HIRA/UBN 1/CABIN 1/ASF 1a）复合物的成员，该复合物独立于复制将变体组蛋白H3.3沉积在染色质上。缺乏HIRA对胚胎干细胞和小鼠卵母细胞中的染色质和基因表达动力学具有普遍影响。在这里，我们描述了有条件的消融Hira在小鼠的心源性中胚层。我们观察到表面水肿、室间隔缺损和房间隔缺损以及胚胎死亡。我们确定了一个心脏基因亚组的失调，特别是肌钙蛋白Tnni 2和Tnnt 3的上调，参与心脏收缩力和Epha 3的表达减少，Epha 3是一种肌肉室间隔和房室垫融合所必需的基因。我们发现HIRA结合胚胎心脏中富含GAGA的DNA基因座，特别是先前描述的由转录因子NKX2.5结合的Tnni 2/Tnnt 3（TTe）的增强子。在体外向心肌细胞分化的胚胎干细胞（ESC）中，观察到HIRA依赖的H3.3富集于TTe。因此，我们在这里表明，HIRA基因表达位点特异性的影响，组蛋白伴侣活性是至关重要的正常心脏发育，冲击的途径，由一个既定的心脏转录因子。
Chromatin remodelling is essential for cardiac development. Interestingly, the role of histone chaperones has not been investigated in this regard. HIRA is a member of the HUCA (HIRA/UBN1/CABIN1/ASF1a) complex that deposits the variant histone H3.3 on chromatin independently of replication. Lack of HIRA has general effects on chromatin and gene expression dynamics in embryonic stem cells and mouse oocytes. Here we describe the conditional ablation of Hira in the cardiogenic mesoderm of mice. We observed surface oedema, ventricular and atrial septal defects and embryonic lethality. We identified dysregulation of a subset of cardiac genes, notably upregulation of troponins Tnni2 and Tnnt3, involved in cardiac contractility and decreased expression of Epha3, a gene necessary for the fusion of the muscular ventricular septum and the atrioventricular cushions. We found that HIRA binds GAGA rich DNA loci in the embryonic heart, and in particular a previously described enhancer of Tnni2/Tnnt3 (TTe) bound by the transcription factor NKX2.5. HIRA-dependent H3.3 enrichment was observed at the TTe in embryonic stem cells (ESC) differentiated toward cardiomyocytes in vitro. Thus, we show here that HIRA has locus-specific effects on gene expression and that histone chaperone activity is vital for normal heart development, impinging on pathways regulated by an established cardiac transcription factor.