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Cell fate choices by Tbx1 in forming the mammalian heart

Tbx1 在形成哺乳动物心脏过程中的细胞命运选择

基本信息

批准号：
10242828
负责人：
BERNICE E MORROW
金额：
$ 60.56万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242828
关键词：
22q11 22q11.2 3-Dimensional APLN gene ATAC-seq Affect Alleles Anterior Aorta Binding Binding Proteins Binding Sites Biological Process Cardiac Cardiac development Cell Differentiation process Cell model Cells ChIP-seq Chromatin Chromosomes Data Data Set Defect DiGeorge Syndrome Ectopic Expression Embryo Embryonic Development Face Gene Expression Profile Gene Proteins General Population Genes Genetic Genetic Transcription Heart Heart Abnormalities Human Genetics Immunofluorescence Immunologic Individual Lung Mammals Maps Mesenchyme Mesoderm Mesoderm Cell Molecular Mus Muscle Muscle Fibers Mutant Strains Mice Mutation Myocardium Neck Neonatal Pathway interactions Patients Penetrance Persistent Truncus Arteriosus Pharyngeal Apparatus Phenocopy Population Population Sizes Process Regulatory Element Risk Factors Shprintzen syndrome Testing Time Tissues base cell behavior cell type conditional mutant congenital heart disorder embryo tissue experimental study functional genomics gastrulation interest mouse model mutant precursor cell progenitor programs receptor single-cell RNA sequencing spatiotemporal stem cells transcription factor transcriptomics

项目摘要

TBX1 encodes a T-box transcription factor required for cardiac development. This gene maps to the chromosome 22q11.2 region that is deleted in patients with DiGeorge syndrome/velo-cardio- facial syndrome or 22q11.2 deletion syndrome (22q11.2DS). Approximately 60% of 22q11.2DS patients have congenital heart disease that mostly affects the cardiac outflow tract. A subset of individuals with a mutation of the TBX1 gene but not a deletion has been identified and they partially phenocopy patients with 22q11.2DS. Inactivation of one allele of Tbx1 in mice results in mild defects, but inactivation of both alleles results in neonatal lethality with a persistent truncus arteriosus, in which the aorta and pulmonary trunk fail to separate. This defect also occurs in 5- 10% of 22q11.2DS patients with congenital heart disease. To understand the function of Tbx1 in mammals, we performed single cell RNA-sequencing (scRNA-seq) of cardiopharyngeal mesoderm progenitor cells within the pharyngeal apparatus. We discovered a multilineage progenitor (MLP) population that expresses genes important for forming the cardiac outflow tract as well as branchiomeric muscles of the face and neck. The MLP population expands at the expense of more differentiated populations when Tbx1 is inactivated in the cardiopharyngeal mesoderm. Our main hypothesis is that Tbx1 is required in the MLP population for progression towards more differentiated states needed for cardiac development. We propose three specific aims to test this hypothesis. In the first aim, we will perform additional scRNA-seq experiments and analyze the complete dataset to understand how the progression of MLP cells are altered in Tbx1 conditional and global mutant mouse embryos. In Aim 2, we will determine where the MLP cells are localized in the embryo. Preliminary data suggests that these cells are localized to the nascent mesenchyme of the elongating pharyngeal apparatus. We will also inactivate Tbx1 specifically within the MLP cells to determine its particular functions. In Aim 3, we will turn to functional genomic studies and will identify open and accessible chromatin for which harbors TBX1 protein binding sites using ATAC-seq and ChIP-seq from embryo tissue. Preliminary data suggests that we are able to identify direct transcriptional target genes. By these three aims, we will understand the molecular functions of TBX1 in the progression of progenitor cells to more differentiated states to build the cardiac outflow tract.

TBX1编码心脏发育所需的T-box转录因子。这个基因映射到