Rtf1-dependent transcriptional regulation of heart development

心脏发育的 Rtf1 依赖性转录调控

• 批准号: 10152694
• 负责人: JAU-NIAN CHEN
• 金额: $ 39.45万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152694
• 关键词: Anterior; Automobile Driving; Binding; Biology; Biotinylation; Cardiac; Cardiac Myoblasts; Cardiac Myocytes; Cardiac development; Cardiovascular Diseases; Cell-Matrix Junction; Cells; ChIP-seq; Chromatin; Defect; Deposition; Development; Developmental Biology; Embryo; Embryonic Heart; Ensure; Epigenetic Process; Event; Extracellular Matrix; Foundations; Gene Expression; Genes; Genetic; Genetic Transcription; Heart; Heart Diseases; Histones; Homeostasis; Impairment; Infant; Injury; Label; Lateral; Lead; Light; Link; Mediating; Mesoderm; Mesoderm Cell; Molecular; Morphogenesis; Mus; Mutate; Mutation; Myocardial; Natural regeneration; Neonatal; Pathogenesis; Population; Proteins; Regenerative Medicine; Research; Role; Sarcomeres; Signal Pathway; Structure; System; Time; Transcriptional Regulation; Transgenic Organisms; Tube; Zebrafish; base; cardiogenesis; cell fate specification; cell type; congenital heart disorder; design; embryonic stem cell; epigenome; histone modification; in vivo; insight; knock-down; mortality; mouse model; novel therapeutic intervention; overexpression; prevent; progenitor; programs; stem; stem cells; transcription factor; transcriptome; transcriptome sequencing; transcriptomics

Project Summary Understanding the molecular mechanisms that drive a pluripotent progenitor cell to differentiate into a specific cell type is germane to Developmental Biology and has important significance in regenerative medicine. Past studies have illustrated that dynamic cardiac transcription programs (CTPs) guide cardiogenesis during development and support cardiac structure and function in homeostasis. While the contributions of key cardiac-specific transcription factors and cardiogenic signaling pathways have been clearly delineated, molecular mechanisms that coordinate the expression of cardiogenic genes to drive myocardial cell specification and direct the maturation of cardiomyocytes remain elusive. Our recent studies using both zebrafish and mouse models indicate that the multi-functional protein Rtf1 is a transcription regulator that orchestrates cardiac gene programs responsible for myocardial specification and differentiation. Knockdown of rtf1 in mouse embryonic stem cells inhibits the cardiac gene program and prevents cardiac differentiation. In vivo, Rtf1 deficient zebrafish and mouse embryos lack myocardial progenitor cells and cannot develop a heart. We also found that Rtf1 deficiency in committed cardiomyocytes impairs cardiac gene program. Collectively, these findings demonstrate a need for Rtf1 activity in myocardial cells at multiple developmental stages. Insights into how Rtf1 regulates dynamic CTPs come from our structure-function analysis showing differential requirements for Rtf1's Plus3 and HMD domains in two temporally distinct cardiogenic events; the Plus3 domain is required for the activation of the CTP and myocardial specification whereas the HMD domain influences histone modifications and directs heart tube morphogenesis. These exciting findings lead to our overarching hypothesis that Rtf1 controls dynamic transcriptional programs in myocardial cells during development by CTP activation and epigenetic modulation. We will employ a set of new transgenic zebrafish lines to define the transcriptional networks of Rtf1 in myocardial progenitors and committed cardiomyocytes. We will investigate how Rtf1's Plus3 domain coordinates the expression of cardiogenic genes to drive the multi-potent mesodermal cells to a myocardial fate (Aim1). We will also interrogate the hypothesis that the Rtf1's HMD domain controls heart tube morphogenesis by influencing the propagation and/or maturation of newly differentiated cardiomyocytes via epigenetic modulation (Aim 2). Successful completion of the proposed projects will provide new mechanistic insights into the transcriptional regulation of myocardial specification and differentiation and will pave the way for the development of novel therapeutic strategies to treat heart diseases.

项目总结

项目成果

Rtf1-dependent transcriptional pausing regulates cardiogenesis.

Rtf1 依赖性转录暂停调节心脏发生。

• DOI: 10.1101/2023.10.13.562296
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Langenbacher,AdamD;Lu,Fei;Tsang,Luna;Huang,ZiYiStephanie;Keer,Benjamin;Tian,Zhiyu;Eide,Alette;Pellegrini,Matteo;Nakano,Haruko;Nakano,Atsushi;Chen,Jau-Nian
• 通讯作者: Chen,Jau-Nian

Rtf1 Transcriptionally Regulates Neonatal and Adult Cardiomyocyte Biology.

RTF1转录调节新生儿和成人心肌细胞生物学。

• DOI: 10.3390/jcdd10050221
• 发表时间: 2023-05-20
• 期刊: Journal of cardiovascular development and disease
• 影响因子: 2.4

Catalytic Enantioselective Synthesis of Guvacine Derivatives through [4 + 2] Annulations of Imines with α-Methylallenoates.

• DOI: 10.1021/acs.orglett.8b02489
• 发表时间: 2018-10-05
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Xu Q;Dupper NJ;Smaligo AJ;Fan YC;Cai L;Wang Z;Langenbacher AD;Chen JN;Kwon O
• 通讯作者: Kwon O

Mitochondrial Calcium Uniporter Deficiency in Zebrafish Causes Cardiomyopathy With Arrhythmia.

• DOI: 10.3389/fphys.2020.617492
• 发表时间: 2020
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Langenbacher AD;Shimizu H;Hsu W;Zhao Y;Borges A;Koehler C;Chen JN
• 通讯作者: Chen JN