Transcriptional regulation of cardiac morphogenesis

摘要 先天性心脏病(CHD)是最常见的出生缺陷。在各种CHD中，单心室 由心室形态发生改变引起的表型临床预后最差。CHDS那个 存在心室形态发生缺陷，导致充氧和去氧血液混合 通过室间隔缺陷(VSD)和/或收缩功能受损，这两者都限制了活力。 目前，对许多致病的分子机制和细胞病因学了解甚少。 各种类型的室性先心病。 Hand1在发育中的左心室(LV)心肌和心肌袖套(MC)中表达 胚胎期(E)E8.5~E13.5。HAND1的建立符合正常左心室和心脏的需要 传导系统形态发生。心肌细胞缺失Hand1导致存活的小鼠出现 CHDS对左心室形态和心功能的影响。HAND1单核苷酸多态已经被 确诊为QRS传导缺陷的患者。这些HAND1多态驻留在 进化上保守的转录增强子，并通过破坏GATA因子DNA结合来发挥作用。Hand1基因 心肌细胞内染色质组织蛋白CTCF功能丧失，下调其表达。 我们的初步数据显示，HAND1被组织成一个单独的拓扑活性结构域(TAD)，该结构域分离 在TAD环内来自其他基因的Hand1与其表达同时进行。浅谈表生的再认识 需要对HAND1基因进行调节，以阐明染色质组织是如何调节 左心室心肌细胞内关键的形态发生转录网络。在其他研究中，我们将确定 HAND1DNA在基因组内的占位，评价心肌细胞内占位表达的变化 基因，并确定与HAND1相互作用的关键转录伙伴，以促进其在脑室中的作用 形态发生。 相关性 导致脑室表型的CHDS的临床结果最差。因此，获得了更好的 了解导致心脏改变的冠心病的病因学和分子机制 形态发生学每年有可能造福成千上万的儿科患者。因为HAND1扮演着关键的角色 在心肌细胞模式方面，深入了解这一未被研究的细胞和分子机制 发展过程对冠心病患者非手术治疗的发展起着至关重要的作用。

ABSTRACT Congenital heart disease (CHD) is the most common birth defect. Among various CHDs, single ventricle phenotypes resulting from altered ventricular morphogenesis have the poorest clinical prognoses. CHDs that present with defective ventricular morphogenesis allow for the mixing of oxygenated and deoxygenated blood via ventricular septal defects (VSDs) and/or impaired contractile function both of which put limits on vitality. Currently, there is a poor understanding of the molecular mechanisms and cellular etiology causative of the many forms of ventricular CHDs. Hand1 is expressed within the developing left ventricle (LV) myocardium and the myocardial cuff (MC) between embryonic day (E) E8.5 and E13.5. HAND1 is established as required for normal LV and cardiac conduction system morphogenesis. Cardiomyocyte deletion of Hand1 results in surviving mice that present with CHDs effecting LV morphology and cardiac function. HAND1 single nucleotide polymorphisms have been identified in patients diagnosed with QRS conduction defects. These HAND1 polymorphisms reside within an evolutionarily conserved transcriptional enhancer, and act by disrupting GATA factor DNA binding. Hand1 gene expression is downregulated by the loss-of function of chromatin organizing protein CTCF within cardiomyocytes. Our preliminary data show that HAND1 is organized into a single topologically active domain (TAD) that isolates Hand1 from other genes within the TAD loop concurrent with its expression. Further examination of the epigenic regulation of the HAND1 locus is needed to elucidate how chromatin organization modulates the expression of critical morphogenetic transcription networks within LV cardiomyocytes. In other studies, we will determine HAND1 DNA occupancy within the genome, evaluate the changes in cardiomyocyte expression within occupied genes, and identify key transcriptional partners that interact with HAND1 to facilitate its role in ventricular morphogenesis. RELEVANCE CHDs resulting in ventricle phenotypes have the poorest clinical outcomes. Thus, gaining a better understanding of the etiology and molecular mechanisms that cause CHDs resulting in altered ventricular morphogenesis has the potential to benefit thousands of pediatric patients annually. As HAND1 plays a key role in cardiomyocyte patterning, gaining insight into the cellular and molecular mechanism of this understudied developmental process is critical for informing the development of non-surgical treatments for CHD patients.