TET-mediated epigenetic regulation in cardiac development.

TET 介导的心脏发育中的表观遗传调控。

• 批准号: 10394202
• 负责人: Yun Huang
• 金额: $ 37.6万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394202
• 关键词: 3-Dimensional; Address; Advanced Development; Affect; Architecture; Binding; Bioinformatics; Biology; Cardiac; Cardiac Myocytes; Cardiac development; Cardiovascular system; ChIP-seq; Chemicals; Chromatin; Chromatin Conformation Capture and Sequencing; Chromatin Loop; Cytosine; DNA; Data; Defect; Development; Developmental Process; Dimensions; Dioxygenases; Enhancers; Environmental Risk Factor; Enzymes; Epigenetic Process; Exhibits; Family; Folic Acid Deficiency; Gene Expression; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genome; Genomic approach; Glycolysis; Goals; Heart; Heart Abnormalities; Heart Diseases; Impairment; Infant; Insulator Elements; Intervention; Knock-out; Knockout Mice; Knowledge; Lead; Link; Location; Mediating; Metabolic; Metabolic Control; Metabolic dysfunction; Metabolism; Methylation; Mission; Mitochondria; Modification; Molecular; Mus; Mutation; Output; Oxides; Pathologic; Pathway interactions; Patients; Play; Positioning Attribute; Prevention; Protein Family; Protein translocation; Proteins; Regulation; Regulatory Element; Regulatory Pathway; Research; Respiration; Rodent; Role; SLC2A1 gene; Scheme; Solid; Stress; Techniques; Testing; Tetanus Helper Peptide; Time; United States National Institutes of Health; Ventricular; base; cardiac regeneration; cardiogenesis; comparative; congenital heart disorder; critical period; demethylation; dietary; embryonic stem cell; empowered; epigenetic regulation; epigenetic therapy; epigenome editing; epigenomics; genomic locus; human embryonic stem cell; in vivo; innovation; insight; mammalian genome; member; methyl group; mouse model; new therapeutic target; novel; novel therapeutic intervention; oxidation; prevent; programs; public health relevance; tool; transcription factor; transcriptional reprogramming; transcriptomics

Project Summary/Abstract Epigenetic regulatory pathways governing gene expression are intimately involved in the regulation of early heart development and cardiac remodeling under pathological stress. Disrupting the cardiac transcriptional networks during early heart development and cardiac regeneration may lead to heart diseases. Among all the known epigenomic modifiers, the Ten-Eleven Translocation (TET) protein family is a relatively new member found to mediate the reversal of DNA methylation in the mammalian genome. The TET dioxygenases (TET1-3) are capable of converting 5-methylcytosine (5mC) to 5-hydroxymethyl-cytosine (5hmC) and further oxidized species, thereby promoting active DNA demethylation. The dynamic changes in 5mC/ 5hmC distributions and transcriptional reprogramming play vital roles during early CM development, a critical period that also provides an optimal time window to study fundamental epigenetic regulatory mechanisms that govern cardiac gene transcription. Our own preliminary studies revealed that genetic depletion of Tet proteins in mice impaired early cardiomyocyte (CM) development. At the cellular level, Tet-deficient CMs further exhibited reduced proliferation and metabolic dysfunction. At the molecular level, upon Tet deletion, we observed massive changes in DNA methylation and a disorganized chromatin architecture that might account for disrupted cardiac transcriptional networks and abnormal expression of key metabolic genes involved in proliferation, glycolysis and mitochondrial respiration in CMs. We hypothesize that the Tet-mediated DNA demethylation pathway is critical for maintaining proper chromatin accessibility and chromatin looping, thereby regulating transcriptional programming to instruct CM development. The immediate availability of a cardiac-specific Tet triple knockout mouse model, as well as a set of innovative tools developed for precise mapping and editing of DNA modifications, has placed us in an extremely competitive position to unravel novel epigenetic regulatory mechanisms controlling CM development. In Aim 1, we will define how Tet/5hmC regulate chromatin accessibility and the binding of key transcriptional factors to their targets to program essential transcriptional outputs and maintain proper CM development. In Aim 2, we will examine how Tet/5hmC regulate chromatin looping by interplaying with enhancer and insulator elements at critical genomic loci to control metabolic gene expression during CM development. Upon completion of our proposed studies, we anticipate to establish a new paradigm by introducing a previously underappreciated dimension in the epigenetic regulation of the cardiovascular system. Findings from our proposed studies will also provide novel insights into the molecular mechanisms responsible for cardiac gene transcription and heart development, thereby forming a solid basis for developing potential epigenetic therapies to prevent and treat congenital heart diseases.

项目总结/文摘

项目成果

Pre-transplantational Control of the Post-transplantational Fate of Human Pluripotent Stem Cell-Derived Cartilage.

• DOI: 10.1016/j.stemcr.2018.06.021
• 发表时间: 2018-08-14
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Lee JY;Matthias N;Pothiawala A;Ang BK;Lee M;Li J;Sun D;Pigeot S;Martin I;Huard J;Huang Y;Nakayama N
• 通讯作者: Nakayama N

Optogenetics for transcriptional programming and genetic engineering.

• DOI: 10.1016/j.tig.2022.05.014
• 发表时间: 2022-12
• 期刊: TRENDS IN GENETICS
• 影响因子: 11.4
• 作者: Lan, Tien-Hung;He, Lian;Huang, Yun;Zhou, Yubin
• 通讯作者: Zhou, Yubin

Red-shifted optogenetics comes to the spotlight.

• DOI: 10.1002/ctm2.807
• 发表时间: 2022-04
• 期刊: Clinical and translational medicine
• 影响因子: 10.6
• 作者: Wang T;Liu S;Huang Y;Zhou Y
• 通讯作者: Zhou Y

Optophysiology: Illuminating cell physiology with optogenetics.

• DOI: 10.1152/physrev.00021.2021
• 发表时间: 2022-07-01
• 期刊: Physiological reviews
• 影响因子: 33.6
• 作者: Tan P;He L;Huang Y;Zhou Y
• 通讯作者: Zhou Y

p53-dependent autophagic degradation of TET2 modulates cancer therapeutic resistance.

• DOI: 10.1038/s41388-018-0524-5
• 发表时间: 2019-03
• 期刊: Oncogene
• 影响因子: 8
• 作者: Zhang J;Tan P;Guo L;Gong J;Ma J;Li J;Lee M;Fang S;Jing J;Johnson G;Sun D;Cao WM;Dashwood R;Han L;Zhou Y;Dong WG;Huang Y
• 通讯作者: Huang Y