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Regulation of embryonic cell fate decision by histone methylation

组蛋白甲基化调控胚胎细胞命运决定

基本信息

批准号：
10021408
负责人：
Juan D Rodriguez
金额：
$ 4.55万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2022-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10021408
关键词：
Affect Animals Caenorhabditis elegans Cell division Cells Cessation of life Child Child Mortality Childhood Chromatin Chromatin Remodeling Factor Congenital Abnormality DNA Packaging Defect Deposition Development Developmental Delay Disorders Disease Ectopic Expression Embryo Embryonic Development Enzymes Epigenetic Process Failure Fertilization Gene Expression Generations Genes Genetic Transcription Grant Heritability Histones Human Individual Infant Inherited Intellectual functioning disability KDM1A gene Kabuki Make-Up Syndrome Learning Maintenance Methylation Methyltransferase Mitotic Modeling Mutation Neurodevelopmental Disorder Oocytes Organ Orthologous Gene Patients Phenotype RNA Interference Regulation Resolution Somatic Cell Specific qualifier value Sterility Syndrome Technology Tissues Totipotency United States blastomere structure causal variant confocal imaging craniofacial genome-wide histone demethylase histone methylation malformation mutant neuronal cell body prevent single-cell RNA sequencing transgenerational epigenetic inheritance

项目摘要

PROJECT SUMMARY: Every year about 7.9 million infants are born with serious birth defects, including craniofacial, intellectual disabilities, organs malformation and developmental delays. More importantly birth defects are the leading cause of child mortality in United States. Recently, many children with birth defects were identified as having mutations in histone modifying enzymes. These include Kabuki Syndrome patients and 3 children with mutations in the histone demethylase LSD1/KDM1. These children all have neurodevelopmental disorders. It is thought that the failure to properly regulate histone methylation in these patients leads to inappropriate transcription. However, it is unclear to what extent inappropriate transcription is heritable within developing embryos. It is also unclear how inappropriate transcription leads to defects. We have recently developed a C. elegans model of inappropriately inherited histone methylation due to failure in epigenetic reprogramming at fertilization. In C. elegans, two epigenetic enzymes, the H3K4me2 demethylase, SPR-5 (ortholog of LSD1), and the H3K9 methyltransferase, MET-2 (ortholog of SetDB1), are maternally deposited into the oocyte. These chromatin modifiers cooperate to reestablish the epigenetic ground state by modifying histone methylation. Progeny of worms lacking SPR-5 and MET-2 accumulate high levels of H3K4me2, resulting in complete sterility and developmental delay, caused by the improper maintenance of germline expression in the soma. Importantly, the C. elegans embryonic lineage is completely invariant. As a result, spr-5;met-2 mutants provide a unique opportunity to understand the rules governing how inappropriate histone methylation affects transcription and cell fate at the single cell level. To do this, I will use confocal imaging to perform automated lineage tracing. This will enable me to detect defects in the timing of cell division, the number of cell divisions, and the survival/death of individual cells in every embryonic lineage. I will combine this with single cell RNA- seq analysis to determine cell by cell, which somatic cells inappropriate express germline genes. By comparing the lineage defects to the inappropriate expression of germline genes in every cell, I will learn the rules governing how inappropriate histone methylation affects transcription and cell fate in developing tissues. Thus, successful completion of this grant will provide a framework for understanding childhood diseases, such as Kabuki Syndrome, caused by mutations in histone modifying enzymes.

项目总结: