权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenomic control of the neural crest cis-regulatory landscape by TGF-beta signaling

TGF-β信号对神经嵴顺式调控景观的表观基因组控制

基本信息

批准号：
10474293
负责人：
Megan Rothstein
金额：
$ 3.9万
依托单位：
CORNELL UNIVERSITY
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：
2021-08-21 至 2023-02-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474293
关键词：
ATAC-seq Automobile Driving Binding Biochemical 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 Light Link MADH2 gene Mediating Molecular Molecular Genetics Morphogenesis Mus Mutate Neural Crest Neural Crest Cell Neurula Nuclear Oral Pathology Phase Play Population Process Proteins Proteomics Regulatory Element Research Role Shapes Signal Transduction Skeleton 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 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

项目摘要

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.

神经嵴是一种多能胚胎细胞群，它产生了大部分颅面骨骼，包括软骨、骨和结缔组织。神经嵴发育失调导致大量大多数颅面畸形和出生缺陷。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。病理学神经嵴的发育是由一个多层次的基因调控网络协调的，祖细胞逐渐定型为神经嵴命运。这个过程不仅需要基因的改变，表达，但也广泛重塑表观基因组景观。染色质重塑事件发生在神经嵴形成的两个相应阶段，诱导和特化之间，部分由先锋因子TFAP 2A的作用。TFAP 2A在细胞周期中激活不同的基因组区域组。神经嵴细胞的诱导和特化，其靶向特异性取决于其与旁系同源蛋白TFAP 2C和TFAP 2B。TFAP 2 A/C和TFAP 2 A/B之间的这种异二聚体开关起作用，推动从诱导到规范的过渡，允许神经细胞的渐进性细胞命运承诺，嵴细胞与这一想法一致，TFAP 2B表达对于驱动转化是必要且充分的。从归纳到规范。TFAP 2B增强子的分析涉及SMAD 2/3核效应子作为TFAP 2B表达的预测驱动因子。这一观察导致了TFAP 2先驱的假设，这些因素将环境信号整合到基因调控网络中，以驱动从诱导到诱导的转变。神经嵴谱系内的规范。本提案的F99阶段旨在调查以下方面的作用： SMAD核效应子及其上游信号系统控制TFAP 2B表达和因此神经嵴规范程序。这项工作将阐明环境刺激如何作用重塑神经嵴内的染色质景观。此外，尽管人们对神经嵴细胞的顺式调控机制的研究已引起了广泛的关注，形成，我们仍然对这些细胞分化为形成面部的骨骼和软骨。神经嵴染色质可及性的单细胞分析区分将允许鉴定对许多面部区室特异的增强子元件。此外，识别特定于隔室的驱动因素将揭示这些调节因素如何作用于协调颅面骨骼内高度复杂和细微结构的形成。最后，该数据可用于获得与以下因素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