Cis regulatory control of avian bill morphogenesis

禽喙形态发生的顺式调控

• 批准号: 10756238
• 负责人: Megan Rothstein
• 金额: $ 9.13万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-07 至 2026-02-06
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10756238
• 关键词: ATAC-seq; Automobile Driving; Binding; Biochemical; Birds; Bone Tissue; Cartilage; Cell Differentiation process; Cells; Cephalic; Chromatin; Complex; Congenital Abnormality; Connective Tissue; Consensus; Craniofacial Abnormalities; Craniosynostosis; Data; Development; Diagnosis; Dimerization; Disease; Dissection; Elements; Enhancers; Environment; Etiology; Event; Face; Gene Expression; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genomic Segment; Genomics; Human; Ligands; Link; MADH2 gene; Mediating; Molecular; Morphogenesis; Mus; Mutate; Neural Crest; Neural Crest Cell; Neurula; Nuclear; Oral; Pathology; Peptide Initiation Factors; Phase; Play; Population; Process; Proteins; Proteomics; Regulatory Element; Research; Role; Shapes; Signal Transduction; Skeleton; Specific qualifier value; Specificity; Stimulus; Structure; System; TFAP2A gene; TFAP2B gene; TFAP2C gene; Testing; Transforming Growth Factor beta; Validation; Work; blastomere structure; bone; cell type; chromatin remodeling; craniofacial; embryo cell; epigenomics; experimental study; extracellular; gene regulatory network; genome wide association study; insight; loss of function; migration; neuroregulation; novel; premature; programs; single cell analysis; skeletal; stem cells; transcription factor

The neural crest is a multipotent embryonic cell population that gives rise to most of the craniofacial skeleton, including cartilage, bone and connective tissue. Misregulation of neural crest development results in the vast majority of craniofacial malformations and birth defects. Thus, uncovering the molecular and genetic underpinnings of neural crest formation has important implications for the diagnosis and treatment of these pathologies. Neural crest development is orchestrated by a multi-level gene regulatory network, in which progenitor cells are progressively committed to a neural crest fate. This process requires not only shifts in gene expression but also an extensive remodeling of the epigenomic landscape. The chromatin remodeling events which occur between two respective stages of neural crest formation, induction and specification, are driven in part by the action of the pioneer factor TFAP2A. TFAP2A activates distinct sets of genomic regions during induction and specification of neural crest cells, and its target specificity is dependent upon its dimerization with paralogous proteins TFAP2C and TFAP2B. This heterodimeric switch between TFAP2A/C and TFAP2A/B acts to drive the transition from induction to specification, allowing for progressive cell fate commitment of neural crest cells. Consistent with this idea, TFAP2B expression is both necessary and sufficient to drive the transition from induction to specification. Analysis of an enhancer of TFAP2B has implicated SMAD2/3 nuclear effectors as predicted drivers of TFAP2B expression. This observation has led to the hypothesis that TFAP2 pioneer factors integrate environmental signals into the gene regulatory network to drive the transition from induction to specification within the neural crest lineage. The F99 phase of this proposal aims to investigate the role of SMAD nuclear effectors and their upstream signaling systems in the control of TFAP2B expression and consequently the neural crest specification program. This work will shed light on how environmental stimuli act to remodel the chromatin landscape within the presumptive neural crest. Moreover, while much focus has been paid to understand the cis-regulatory control of neural crest cell formation, we still have very little insight on the molecular mechanisms by which these cells differentiate to form the bone and cartilage of the face. Single-cell analysis of chromatin accessibility in neural crest differentiation will allow for the identification of enhancer elements specific to numerous facial compartments. Furthermore, identification of compartment-specific drivers will reveal how these regulatory factors act to orchestrate the formation of highly complex and nuanced structures within the craniofacial skeleton. Ultimately, this data may be used to gain a mechanistic understanding of the etiology of congenital birth defects linked to the misregulation of craniofacial morphogenesis.

神经嵴是多能胚胎细胞群，产生大部分颅面骨骼， 包括软骨、骨和结缔组织。神经嵴发育的失调导致了巨大的 大多数颅面部畸形和出生缺陷。因此，揭示分子和遗传 神经嵴形成的基础对于这些疾病的诊断和治疗具有重要意义 病理学。神经嵴发育是由多级基因调控网络精心策划的，其中 祖细胞逐渐走向神经嵴命运。这个过程不仅需要基因的转变 表达，也是表观基因组景观的广泛重塑。染色质重塑事件 发生在神经嵴形成、诱导和规范的两个相应阶段之间，被驱动 部分是由于先锋因子 TFAP2A 的作用。 TFAP2A 激活不同组的基因组区域 神经嵴细胞的诱导和特化，其靶标特异性取决于其与 旁系同源蛋白 TFAP2C 和 TFAP2B。 TFAP2A/C 和 TFAP2A/B 之间的异二聚体开关起作用 驱动从诱导到规范的转变，允许神经细胞的渐进细胞命运承诺 嵴细胞。与这个想法一致，TFAP2B 表达对于驱动转变既是必要的也是充分的 从归纳到规范。 TFAP2B 增强子的分析暗示 SMAD2/3 核效应子 作为 TFAP2B 表达的预测驱动因素。这一观察结果得出了这样的假设：TFAP2 先驱 因素将环境信号整合到基因调控网络中，以驱动从诱导到转变的转变 神经嵴谱系内的规范。该提案的 F99 阶段旨在调查 SMAD 核效应子及其上游信号系统在控制 TFAP2B 表达和 因此，神经嵴规范程序。这项工作将揭示环境刺激如何发挥作用 重塑假定的神经嵴内的染色质景观。 此外，虽然人们对神经嵴细胞的顺式调节控制给予了很多关注 的形成，我们对这些细胞分化成的分子机制仍然知之甚少。 形成面部的骨骼和软骨。神经嵴染色质可及性的单细胞分析 分化将允许识别许多面部区室特有的增强子元件。 此外，识别特定于车厢的驱动因素将揭示这些调节因素如何发挥作用 协调颅面骨骼内高度复杂和细致的结构的形成。最终， 该数据可用于获得对与以下疾病相关的先天性出生缺陷的病因学的机械理解： 颅面形态发生的失调。