The role of epigenetic modifiers in regulating the developmental plasticity of cranial neural crest cells

表观遗传修饰剂在调节颅神经嵴细胞发育可塑性中的作用

• 批准号: 10352461
• 负责人: Kristin Artinger
• 金额: $ 2.37万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352461
• 关键词: ATAC-seq; Binding Sites; Cartilage; Cell Differentiation process; Cell Lineage; Cells; Cephalic; Chondrocytes; Chromatin; Chromatin Remodeling Factor; Competence; Congenital Abnormality; DNA Binding; Development; Developmental Biology; Differentiated Gene; EVI1 gene; Embryo; Epigenetic Process; Etiology; Exhibits; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Human; Knowledge; Link; Mission; Molecular; Nature; Neural Crest; Neural Crest Cell; Neuroglia; Neuronal Differentiation; Neurons; Peripheral Nervous System; Protein Family; Proteins; Public Health; Regenerative Medicine; Regulation; Research; Role; Series; Signal Transduction; Site; System; Testing; Time; Tissues; Transcriptional Regulation; Trigeminal System; United States National Institutes of Health; XCL1 gene; Zebrafish; bone; cartilage cell; cell type; chromatin modification; craniofacial; craniofacial tissue; developmental plasticity; disability; gene regulatory network; histone methyltransferase; histone modification; insight; loss of function; migration; morphogens; multipotent cell; mutant; neuromechanism; progenitor; recruit; repaired; single cell sequencing; single-cell RNA sequencing; stem; stem cells; tissue repair; transcription factor; transcriptome; transcriptome sequencing

Summary How stem progenitor cells maintain plasticity for proper cell fate determination over developmental time is a fundamental question in developmental biology and regenerative medicine. Cranial neural crest cells (cNCCs) are an excellent example of a well defined cellular lineage transition in which multipotent cells step through a series of more restricted progenitors to give rise to diverse array of differentiated cell types, including neurons and glia of the peripheral nervous system as well as craniofacial cartilage and bone. Thus, understanding the genetic and epigenetic regulators in cNCC development is key to understanding how cell fate is determined as well as how cells can be reprogrammed. We hypothesize that the cNCC cartilage/neuron/glial progenitor retains plasticity through developmental time and cNCC fate acquisition is controlled by regulation of chromatin accessibility by prdm3. The rationale for the proposed studies is that an in-depth understanding of the specific factors involved in cNCC lineage transitions will provide insights into both normal developmental plasticity of cNCCs as well as how progenitors can be reprogramed for tissue repair. We will test this hypothesis in the following specific aims: 1) Test the hypothesis that prdm3 acts as a molecular cell fate switch during cNCC differentiation. Here we will test the hypothesis that prdm3 activity is required in cNCCs cell autonomously to promote the temporal recruitment of progenitors to cartilage by repressing neuronal cell fate. 2) Test the hypothesis that the cartilage/neuronal/glial (CNG) progenitor retains plasticity through developmental time and can be reprogramed by loss of prdm3. In Aim 2, hypothesis that CNG progenitors retain plasticity over developmental time and into larval stages and are reprogramed with loss of prdm3. 3) Test the hypothesis that Prdm3 regulates the timing of cNCC differentiation by controlling of genomic accessibility. In Aim 3, we will test the hypothesis that loss of Prdm3 leads to global alterations in chromatin state at cNCC progenitor genes, which in turn controls the timing of differentiation. 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 normal developmental plasticity of cNCCs such that tissue reprograming can be developed for the repair of damaged craniofacial tissues.

概括 茎祖细胞如何保持可塑性以在发育时间内确定适当的细胞命运是一个 发育生物学和再生医学中的基本问题。颅神经rest细胞（CNCCS） 是定义明确的细胞谱系过渡的一个很好的例子，其中多能细胞通过 一系列受限制的祖细胞产生各种分化细胞类型，包括神经元 周围神经系统以及颅面软骨和骨骼的神经胶质。因此，了解 CNCC发育中的遗传和表观遗传调节剂是理解细胞命运的关键 以及如何重新编程细胞。我们假设CNCC软骨/神经元/神经胶质祖先 通过发育时间保留可塑性，CNCC命运的采集受到调节 PRDM3的染色质可访问性。拟议研究的理由是深入理解 CNCC谱系过渡中涉及的特定因素中，将提供对这两种正常发展的见解 CNCC的可塑性以及如何对祖细胞进行重新编程以进行组织修复。我们将测试这个 假设以下特定目的：1）检验以下假设：PRDM3充当分子细胞命运 在CNCC分化过程中切换。在这里，我们将测试CNCC中需要PRDM3活动的假设 通过抑制神经元细胞来促进祖细胞的时间募集到软骨 命运。 2）检验软骨/神经/神经胶质（CNG）祖细胞可保留可塑性的假设 发育时间，可以通过损失PRDM3进行重编程。在AIM 2中，CNG的假设 祖先在发育时间内和幼虫阶段保持可塑性 PRDM3。 3）检验PRDM3通过控制CNCC分化的时间的假设 基因组可及性。在AIM 3中，我们将检验以下假设：PRDM3的损失会导致全球变化 CNCC祖细胞基因的染色质状态，进而控制分化的时间。在一起，这些 研究将揭示CNCC在开发过程中如何区分特定细胞类型的基本信息。 该提案的结果有可能揭示对正常发展的重要新见解 CNCC的可塑性可以开发组织重编程以修复受损的颅面 组织。