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.

神经嵴是一个多能胚胎细胞群，它产生了大部分颅面骨骼，