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：
10316019
负责人：
Kristin Artinger
金额：
$ 43万
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 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10316019
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 Regulator Genes 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 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.

细胞如何在正确的时间和地点进行指定和区分是一个基本问题发展生物学。颅神经rest细胞（CNCC）是理解这一点的绝佳模型系统由于祖细胞的多能性质，过程通常不受限制地发育潜力具有已知的谱系和衍生物，并定义了基因调节网络。除了基因网络，表观遗传调节剂可以影响众多靶基因的表达，并可能有助于解释具有相同基因型的个体之间的外观和表型的差异。这很重要，因为神经rest发育中的缺陷是许多人类先天性先天性出生缺陷的基础，例如与或没有口感和许多颅面综合征。因此，了解中的遗传和表观遗传调节剂 CNCC开发是了解细胞命运如何确定的关键。我们假设PRDM 旁系同源物通过相反调节下游靶标调节全局基因表达，包括Wnt 途径成分，以控制CNCC谱系内软骨/骨分化的时机。拟议研究的理由是，对正常CNCC发展的深入了解提供有关正常生物学和神经rest相关的先天缺陷的病因的见解，其中许多是被认为是由CNCC异常引起的。我们将在以下特定目的中检验该假设：1）测试 PRDM蛋白在Wnt信号传导上游作用以控制CNCC的时机的假设分化为软骨细胞。我们将测试CNCC中需要的假设prom旁同产活动细胞自主信号传导的上游以促进软骨细胞的分化。 2）测试 PRDM3和PRDM16遗传相互作用以调节CNCC基因表达和染色质可及性。在AIM 2中，PRDM3和PRDM16基因相互作用以控制基因的假设通过调节转录和染色质修饰的表达，在CNCC和Wnt基因靶标上进行表达。 3）检验PRDM3通过控制的时间来调节全局基因表达的假设 PRDM16的基因组可及性。在AIM 3中，我们将检验以下假设：PRDM3的损失导致全球 CNCC祖细胞基因染色质状态的改变，通过整个PRDM16的结合变化基因组控制CNCC分化为软骨细胞的限制。这些研究将在一起揭示CNCC在开发过程中如何区分特定细胞类型的基本信息。结果该提案有可能揭示有关CNCC开发以及如何这些的重要新见解疾病中的过程出错，希望为设计策略设计提供基础对于神经rest相关的先天缺陷。