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.

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具有最差的临床表现。CHD， 存在心室形态发生缺陷，允许氧合血和脱氧血混合 通过室间隔缺损（VSD）和/或收缩功能受损，这两者都限制了生命力。 目前，人们对许多疾病的分子机制和细胞病因学了解甚少。 心室CHD的形式。 Hand 1在发育中的左心室（LV）心肌和心肌袖（MC）内表达 在胚胎日（E）E8.5和E13.5之间。根据正常LV和心脏的需要建立HAND 1 传导系统形态发生Hand 1的心肌细胞缺失导致存在以下缺陷的小鼠存活： CHD影响LV形态和心功能。HAND 1单核苷酸多态性已经被 在诊断为QRS传导缺陷的患者中发现。这些HAND 1多态性存在于 进化上保守的转录增强子，并通过破坏加塔因子DNA结合而起作用。Hand 1基因 表达被心肌细胞内染色质组织蛋白CTCF功能的丧失下调。 我们的初步数据表明，HAND 1被组织成一个单一的拓扑活性结构域（topologically active domain，简写为ESTs）， Hand 1在其表达的同时，从其他基因中分离。进一步研究表观遗传 HAND 1基因座的调控需要阐明染色质组织如何调节 关键的形态发生转录网络。在其他研究中，我们将确定 HAND 1 DNA在基因组内的占有率，评估心肌细胞表达的变化， 基因，并确定与HAND 1相互作用的关键转录伙伴，以促进其在心室肌中的作用。 形态发生 相关性 导致心室表型的CHD具有最差的临床结局。因此，获得更好的 了解导致CHD的病因和分子机制，导致心室改变 形态发生每年有可能使成千上万的儿科患者受益。由于HAND 1扮演着关键角色， 在心肌细胞的图案，获得深入了解这种欠研究的细胞和分子机制， 发展过程是至关重要的，为冠心病患者的非手术治疗的发展提供信息。