Combinatorial Regulation of Gene Networks During Cardiac Development and Disease

心脏发育和疾病过程中基因网络的组合调控

• 批准号: 10245023
• 负责人: DEEPAK SRIVASTAVA
• 金额: $ 273.2万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245023
• 关键词: 3-Dimensional; Address; Adult; Anatomy; Architecture; Bioinformatics; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cardiac development; Cardiovascular Diseases; Cells; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Code; Complex; Congenital Abnormality; Congenital Heart Defects; DNA; DNA Binding; Data Set; Development; Dimerization; GATA4 gene; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genome engineering; Genomics; Heart Diseases; Heart failure; Human; Intervention; Knowledge; Location; Morphogenesis; Mutate; Mutation; Nuclear; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Output; Paper; Play; Post-Translational Protein Processing; Process; Program Research Project Grants; Proteins; Proteomics; Publishing; Reading; Regenerative Medicine; Regulation; Repression; Role; Signal Transduction; Specificity; System; Testing; Transcription Factor 3; Transcriptional Regulation; cardiogenesis; causal variant; chromatin remodeling; combinatorial; congenital heart disorder; disease-causing mutation; genome-wide; genomic locus; human disease; induced pluripotent stem cell; interest; member; mortality; multidisciplinary; myocardin; protein protein interaction; recruit; regenerative cell; synergism; transcription factor

PROJECT SUMMARY/ABSTRACT OVERALL COMPONENT Cardiovascular disease is the most common cause of mortality in adults, and congenital heart defects (CHDs) are the most common form of birth defects. An important concept that has emerged in recent years is that dysregulation of cardiac transcription factor (TF) networks and related chromatin remodeling machinery contributes to CHDs and heart failure. Forced expression of the core members of the TF network is sufficient to reprogram non-myocytes into cardiomyocyte-like cells for regenerative medicine purposes, suggesting a combinatorial code for determining cell fate. As genome-wide roles for critical TFs are being discovered, a conceptual understanding of their function in higher order DNA organization is emerging. Evidence that the three-dimensional organization of DNA promotes activation or repression of genomic loci has raised the question of how cooperative protein-protein interactions involving TF and chromatin remodeling complexes participate in this process. We have integrated a multidisciplinary team of developmental cardiologists, computational biologists, and systems biologists, with expertise in CRISPR/Cas9 genome engineering in human iPS cells, to investigate how the genome is regulated by TFs and chromatin remodelers to control cardiac gene expression and fate. The specific hypotheses that we test in this proposal, which involve a combination of core cardiac TFs that interact with one another to coordinately regulate cardiac gene expression, are as follows: 1) that the cardiac TFs GATA4 and TBX5 interact in a lineage-specific fashion with the nuclear pore complex to regulate the 3D genomic architecture and subsequent transcriptional output; 2) that specific BAF chromatin remodeling complexes form dynamically to coordinate regulation of distinct aspects of cardiac morphogenesis and lineage decisions through interaction with cardiac TFs; and 3) that the MEF2C-myocardin complex, which interacts with GATA4, TBX5 and BAF60c, recruits a transcriptional complex influenced by upstream signaling and myocardin dimerization to regulate cardiac gene expression. To address these questions, we have integrated unique expertise in the study of protein-protein interactions and post-translational modifications through the Advanced Proteomics Core; the ability to analyze complex datasets of PPIs, DNA-binding, and transcriptional output related to transcriptional regulators through the Advanced Bioinformatics Core; and the ability to leverage state-of-the-art genome engineering approaches through the Genome Engineering Core. The questions in this proposal will be studied in the context of human disease-causing mutations to reveal underlying mechanisms and paradigms that control normal and abnormal cardiogenesis. The integrated knowledge developed here will enable a clear reading of the transcriptional “code” for cardiac cell fate determination and differentiation that may be leveraged for interventions in CHD and for regenerative medicine.

项目总结/文摘