Transcriptional regulation of cardiac morphogenesis

心脏形态发生的转录调控

• 批准号: 10495950
• 负责人: Anthony B. Firulli
• 金额: $ 53.24万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10495950
• 关键词: Alleles; BHLH Protein; Biological Assay; Blood; CCCTC-binding factor; Cardiac; Cardiac Myocytes; Cardiac conduction system; Cell Lineage; Cell physiology; Cells; Chromatin; Clinical; Communication; Complex; Congenital Abnormality; DNA; DNA Binding; Data; Defect; Detection; Development; Developmental Process; Diagnosis; Disease; Down-Regulation; Elements; Embryo; Embryonic Heart; Engineering; Enhancers; Epigenetic Process; Epitopes; Etiology; GATA4 gene; Gene Expression; Gene Expression Profile; Genes; Genetic Polymorphism; Genetic Transcription; Genome; Growth; Heart; Human; Immunoprecipitation; Impairment; Knock-out; Left ventricular structure; Modeling; Modification; Molecular; Morphogenesis; Morphology; Mus; Myocardial; Myocardium; Neural Crest; Outcome; Papillary; Patients; Pattern; Phenotype; Play; Process; Proteins; Publishing; Purkinje Cells; Regulation; Role; Single Nucleotide Polymorphism; Single ventricle congenital heart disease; Site; Specific qualifier value; Structure; Systems Development; Testing; Transcript; Transcriptional Regulation; Transposase; Ventricular; Ventricular Septal Defects; cardiogenesis; cell type; chromatin immunoprecipitation; chromosome conformation capture; clinical prognosis; cofactor; conditional knockout; congenital heart disorder; embryonic stem cell; epigenetic regulation; gene regulatory network; heart function; human data; human embryonic stem cell; in vivo; insight; loss of function; myocyte-specific enhancer-binding-factor 2C; papillary muscle; pediatric patients; programs; transcription factor; transcriptome; transcriptomics

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.

抽象的 先天性心脏病（CHD）是最常见的先天缺陷。在各种CHD中，单脑室 心室形态发生改变引起的表型的临床预后最差。那个 存在有缺陷的心室形态发生，可以混合氧化和脱氧的血液 通过心室间隔缺陷（VSD）和/或收缩功能受损，这两者都限制了活力。 目前，对许多分子机制和细胞病因的理解不足 心室CHD的形式。 Hand1在发育中的左心室（LV）心肌和心肌袖口（MC）中表达 在胚胎日（E）E8.5和E13.5之间。 Hand1是根据正常LV和心脏的要求建立的 传导系统形态发生。 Hand1的心肌细胞缺失导致生存的小鼠存在 CHD影响LV形态和心脏功能。 Hand1单核苷酸多态性已经 在诊断为QRS传导缺陷的患者中鉴定出来。这些手1多态性位于 进化保守的转录增强子，并通过破坏GATA因子DNA结合起作用。 Hand1基因 表达被心肌细胞内染色质组织蛋白CTCF的功能丧失。 我们的初步数据表明，HAND1被组织成一个单个拓扑主动域（TAD），该结构域分离出来 TAD环内其他基因的手1与其表达并发。进一步检查 需要调节手的1个基因座，以阐明染色质组织如何调节表达 LV心肌细胞内的关键形态发生转录网络。在其他研究中，我们将确定 基因组中的Hand1 DNA占用率，评估占据内心肌细胞表达的变化 基因，并确定与Hand1相互作用的关键转录伙伴以促进其在心室中的作用 形态发生。 关联 导致心室表型的芯片具有最差的临床结局。因此，获得更好的 了解导致CHD导致心室改变的病因和分子机制 形态发生有可能使数千名小儿患者受益。正如Hand1扮演的关键角色 在心肌细胞模式中，洞悉该研究的细胞和分子机制 发展过程对于告知冠心病患者非手术治疗的发展至关重要。