The Epigenetic Landscape of Heart Development

心脏发育的表观遗传景观

• 批准号: 8711538
• 负责人: Laurie A Boyer
• 金额: $ 192.57万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711538
• 关键词: Address; Affect; Algorithms; Alleles; Animals; Atlases; Binding; Bioinformatics; Biological; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cells; ChIP-seq; Child; Childhood; Chromatin; Chromatin Remodeling Factor; Collaborations; Commit; Communities; Complex; Computing Methodologies; Congenital Abnormality; Congenital Heart Defects; DNA Sequencing Facility; Data; Data Set; Development; Developmental Biology; Disease; Doctor of Philosophy; Embryo; Embryonic Heart; Ensure; Epigenetic Process; Etiology; Functional RNA; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Transcription; Genome; Genomics; Grant; Histones; Human; Human Genome; Inherited; Institutes; Instruction; Knock-out; Laboratories; Lead; Link; Maps; Massachusetts; Mesoderm; Methods; MicroRNAs; Modeling; Modification; Molecular Profiling; Morphogenesis; Mus; Mutation; National Heart, Lung, and Blood Institute; Nucleosomes; Pan Genus; Patients; Physiology; Positioning Attribute; Post-Translational Regulation; Principal Investigator; Publications; Regulation; Regulatory Pathway; Reporting; Research; Resolution; Role; Sequence Analysis; Statistical Methods; Stem cells; Talents; Technology; Time; Training; Transcription factor genes; Transcriptional Regulation; United States National Institutes of Health; Work; base; cardiogenesis; cell type; chromatin remodeling; congenital heart disorder; deep sequencing; distributed data; embryonic stem cell; experience; genome-wide; high throughput analysis; histone modification; human disease; improved; induced pluripotent stem cell; innovation; insight; loss of function; mRNA Expression; mammalian genome; member; mortality; new technology; postnatal; programs; promoter; stem cell biology; success; tool; transcription factor

DESCRIPTION (provided by applicant): Congenital heart defects (CHDs) are among the most common and most devastating birth defects in humans. Networks of transcription factors regulate cardiac cell fate and morphogenesis, and dominant mutations in transcription factor genes lead to most instances of inherited CHD. The mechanisms underlying CHDs that result from disruption of these networks remain to be identified, but regulation of gene expression within a relatively narrow developmental window is clearly essential for normal cardiac morphogenesis. In addition to transcription factors, epigenetic regulation via histone modifications, chromatin remodeling, and non-coding RNAs have key roles in modulating gene expression programs. Elucidating on a genome scale the physical and functional interactions between transcription factors and epigenetic regulators will considerably enhance our understanding of the control of heart development and will have important implications for understanding the mechanistic basis of CHDs. We propose a project as part of the NHLBI Heart Development consortium to provide an integrated epigenetic landscape for heart development, with a focus on CHD-related genes. We propose three major aims. Aim 1: Define genome-wide occupancy maps of transcription factors with known roles in cardiac development and human disease, and epigenetic regulators of transcription, in differentiating cardiomyocytes. Aim 2: Define the global function of transcriptional and epigenetic regulation in heart development and congenital heart disease. We will examine the effect of loss of function of cardiac transcription factors on epigenetic regulation, and alterations in epigenetic regulation in disease-specific induced pluripotent cells from CHD patients. We will also evaluate the global role of histone modifications in mouse heart development. Aim 3; Integrate microRNA expression and function into the regulatory networks governing cardiac development. High-resolution occupancy maps from Aims 1 and 2 will be analyzed specifically for miRNA promoter occupancy and combined with quantitative sequencing of miRNAs in differentiating cardiomyocytes. We will study the function of highly altered miRNAs, specifically those that target disease-causing cardiac transcription factors. Our studies will yield an important and transformative epigenetic atlas of heart development, which will link for the first time transcriptional and epigenetic regulators in a comprehensive network that will illuminate mechanisms underlying CHDs. RELEVANCE (See instructions): The proposed project will for the first time allow a new understanding of the gene networks that underlie congenital heart disease. Congenital heart disease is the most serious childhood illness, affecting 1% of children, and leading to significant mortality and long-term illness. However the underlying causes of these diseases are not understood. Our project will link the so-called "epigenetic regulators" that control how genes are turned on or off, to congenital heart disease, bringing new important insights into these diseases.

描述（由申请人提供）：

项目成果

Investigating the transcriptional control of cardiovascular development.

• DOI: 10.1161/circresaha.116.302832
• 发表时间: 2015-02-13
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Kathiriya IS;Nora EP;Bruneau BG
• 通讯作者: Bruneau BG

Predicting 3D genome folding from DNA sequence with Akita.

• DOI: 10.1038/s41592-020-0958-x
• 发表时间: 2020-11
• 期刊: Nature methods
• 影响因子: 48
• 作者: Fudenberg G;Kelley DR;Pollard KS
• 通讯作者: Pollard KS

Improved Sendai viral system for reprogramming to naive pluripotency.

• DOI: 10.1016/j.crmeth.2022.100317
• 发表时间: 2022-11-21
• 期刊: Cell reports methods

Expandable Cardiovascular Progenitor Cells Reprogrammed from Fibroblasts.

• DOI: 10.1016/j.stem.2016.02.001
• 发表时间: 2016-03-03
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Zhang Y;Cao N;Huang Y;Spencer CI;Fu JD;Yu C;Liu K;Nie B;Xu T;Li K;Xu S;Bruneau BG;Srivastava D;Ding S
• 通讯作者: Ding S

How old is my gene?

• DOI: 10.1016/j.tig.2013.07.001
• 发表时间: 2013-11
• 期刊: TRENDS IN GENETICS
• 影响因子: 11.4
• 作者: Capra, John A.;Stolzer, Maureen;Durand, Dannie;Pollard, Katherine S.
• 通讯作者: Pollard, Katherine S.