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Genetic and epigenetic regulation of cranial neural crest differentiation

颅神经嵴分化的遗传和表观遗传调控

基本信息

批准号：
10442617
负责人：
Kristin Artinger
金额：
$ 42.6万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-02-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442617
关键词：
ATAC-seq Abnormal Cell Affect Binding Binding Sites Biological Models Biology Cartilage Cell Differentiation process Cell Lineage Cells Cephalic Chondrocytes Chromatin Chromatin Remodeling Factor Cleft Lip Cleft Palate Competence Congenital Abnormality Craniofacial Abnormalities DNA DNA Binding Data Defect Development Developmental Biology Disease Due Process EVI1 gene Embryo Enhancers Epigenetic Process Etiology Exhibits Family Foundations GATA1 gene Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Genome Genomics Genotype Goals Growth Histones Human Individual Knock-out Knowledge Limes Link Mission Modification Mus Mutation Nature Neural Crest Neural Crest Cell Palate Pathway interactions Penetrance Phenotype Play Process Protein Family Proteins Public Health Regulation Research Role Signal Transduction Site Specific qualifier value Structural Congenital Anomalies Syndrome Testing Therapeutic Time Tissues United States National Institutes of Health WNT Signaling Pathway Zebrafish bone cell type chromatin modification craniofacial craniofacial complex craniofacial structure design disability epigenetic regulation gain of function gene network gene regulatory network histone methyltransferase human disease insight mutant neuromechanism novel paralogous gene stem cells transcription factor transcriptome transcriptome sequencing

项目摘要

How cells become specified and differentiate at the correct time and place is a fundamental question in developmental biology. Cranial neural crest cells (cNCCs) are an excellent model system to understand this process due to the multipotent nature of the progenitor cells, generally unrestricted developmental potential with known lineage and derivatives, and defined gene regulatory networks. In addition to the gene networks, epigenetic regulators can affect the expression of numerous target genes and may help to explain the differences in penetrance and phenotype between individuals with the same genotype. This is important since defects in neural crest development underlie many human congenital birth defects, such as cleft lip with or without palate and many craniofacial syndromes. Thus, understanding the genetic and epigenetic regulators in cNCC development is key to understanding how cell fate is determined. We hypothesize that PRDM paralogs regulate global gene expression by regulating downstream targets oppositely, including Wnt pathway components, to control the timing of cartilage/bone differentiation within the cNCC lineage. The rationale for the proposed studies is that an in depth understanding of normal cNCC development will provide insights into normal biology and the etiology of neural crest-associated birth defects, many of which are thought to arise from cNCC abnormalities. We will test this hypothesis in the following specific aims: 1) Test the hypothesis that PRDM proteins act upstream of Wnt signaling to control the timing of cNCC differentiation into chondrocytes. We will test the hypothesis PROM paralog activity is required in cNCCs cell autonomously upstream of Wnt signaling to promote differentiation of chondrocytes. 2) Test the hypothesis that Prdm3 and Prdm16 genetically interact to regulate cNCC gene expression and chromatin accessibility. In Aim 2, hypothesis that Prdm3 and Prdm16 genetically interact to control gene expression via regulating transcription and chromatin modification specifically at cNCC and Wnt gene targets. 3) Test the hypothesis that Prdm3 regulates global gene expression by controlling the timing of genomic accessibility of Prdm16. In Aim 3, we will test the hypothesis that loss of Prdm3 leads to global alterations in chromatin state at cNCC progenitor genes via changes in binding of Prdm16 throughout the genome, which controls the liming of cNCC differentiation into chondrocytes. Together, these studies will reveal basic information of how cNCCs differentiate into specific cell types during development. The results of this proposal have the potential to reveal important new insights into cNCC development and how these processes go wrong in disease, with the hope of providing a foundation for the design of therapeutic strategies for neural crest associated birth defects.

细胞是如何在正确的时间和地点被指定和分化的