TET-mediated epigenetic regulation in cardiac development.

TET 介导的心脏发育中的表观遗传调控。

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要控制基因表达的表观遗传调节途径与早期的调节密切相关在病理压力下心脏发育和心脏重塑。破坏心脏转录早期心脏发展和心脏再生期间的网络可能导致心脏病。在所有已知的表观基因组修饰剂，十个易位（TET）蛋白质家族是一个相对较新的成员发现可以介导哺乳动物基因组中DNA甲基化的逆转。 TET二氧酶（TET1-3）能够将5-甲基胞嘧啶（5MC）转换为5-羟基甲基 - 胞嘧啶（5HMC），并进一步氧化物种，从而促进活性DNA脱甲基化。 5MC/ 5HMC分布的动态变化和转录重编程在早期CM开发期间发挥至关重要的作用，这也提供了一个关键时期研究心脏基因的基本表观遗传调节机制的最佳时间窗口转录。我们自己的初步研究表明，小鼠中TET蛋白的遗传耗竭早期受损心肌细胞（CM）发育。在细胞水平上，缺乏TET的CMS进一步表现出降低增殖和代谢功能障碍。在分子水平上，在TET缺失时，我们观察到了大量 DNA甲基化和混乱的染色质结构的变化，可能会破坏心脏转录网络和与增殖有关的关键代谢基因的异常表达， CMS中的糖酵解和线粒体呼吸。我们假设TET介导的DNA脱甲基化途径对于维持适当的染色质可及性和染色质循环至关重要，从而调节转录编程指导CM开发。心脏特异性TET的立即可用性三重基因敲除鼠标模型以及开发用于精确映射和编辑的创新工具 DNA修饰使我们处于竞争极具竞争力的位置，以揭示新的表观遗传调节控制CM开发的机制。在AIM 1中，我们将定义TET/5HMC如何调节染色质可访问性和关键转录因子与目标的结合以编程基本转录输出并保持适当的CM开发。在AIM 2中，我们将检查TET/5HMC如何调节染色质通过与临界基因组基因座增强子和绝缘元素相互作用以控制代谢基因的循环循环 CM发育过程中的表达。我们提出的研究完成后，我们预计将建立一个通过在表观遗传调节中引入先前未被评估的维度来提出新的范式心血管系统。我们提出的研究的发现还将为分子提供新的见解负责心脏基因转录和心脏发育的机制，从而形成坚实的基础为了开发潜在的表观遗传疗法，以预防和治疗先天性心脏病。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

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

Rewiring Calcium Signaling for Precise Transcriptional Reprogramming.

DOI：
10.1021/acssynbio.7b00467
发表时间：
2018-03-16
期刊：
ACS synthetic biology
影响因子：
4.7
作者：
Nguyen NT;He L;Martinez-Moczygemba M;Huang Y;Zhou Y
通讯作者：
Zhou Y

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

Optophysiology: Illuminating cell physiology with optogenetics.