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.

神经脊是一个多能的胚胎细胞群，它形成了大部分头面部骨骼， 包括软骨、骨和结缔组织。对神经脊发育的错误调节导致 大多数头面部畸形和出生缺陷。因此，揭示了分子和基因 神经脊形成的基础对该病的诊断和治疗具有重要意义。 病理学。神经脊的发育是由一个多层次的基因调控网络协调的，在这个网络中 祖细胞逐渐走向神经顶峰的命运。这一过程不仅需要基因的转移 表达，但也是对表观基因组景观的广泛重塑。染色质重塑事件 它们发生在神经脊形成的两个不同阶段，即诱导和规范，被驱动进入 部分是由于先驱因子TFAP2A的作用。TFAP2A激活不同的基因组区域 神经脊细胞的诱导和定向化，其靶向性取决于其与 同源蛋白Tfap2c和TFAP2b。TFAP2A/C和TFAP2A/B之间的异二聚体开关起作用 推动从诱导到规范的转变，允许神经递进的细胞命运承诺 冠状细胞。与这一想法一致，TFAP2B的表达对于推动过渡是必要的，也是充分的 从归纳到规范。分析TFAP2B的增强子与Smad2/3核效应相关 作为TFAP2B表达的预测驱动因素。这一观察结果导致了TFAP2先驱的假设 因子将环境信号整合到基因调控网络中，推动从诱导到 神经脊谱系内的规范。这项提案的F99阶段旨在调查 Smad核效应因子及其上游信号系统在TFAP2B表达和调控中的作用 因此，神经脊规范程序。这项工作将阐明环境刺激是如何起作用的 在假定的神经脊内重塑染色质景观。 此外，虽然人们对神经脊细胞顺式调控的了解很多，但 形成，我们仍然对这些细胞分化为 形成面部的骨骼和软骨。神经脊染色质可及性的单细胞分析 区分将允许识别许多面部隔室所特有的增强剂成分。 此外，识别特定于车厢的司机将揭示这些监管因素如何作用于 协调在头面部骨骼内形成高度复杂和细微差别的结构。最终， 这些数据可以用来从机制上理解先天性出生缺陷的病因学。 颅面形态发生的失调。