Transcriptional Regulatory Networks of Craniofacial Development

颅面发育的转录调控网络

• 批准号: 10432118
• 负责人: Hong Li
• 金额: $ 13.01万
• 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: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10432118
• 关键词: ATAC-seq; Address; Adopted; Affect; Age; Automobile Driving; Bioinformatics; Biological Assay; Biological Models; Biology; Cartilage; Cells; ChIP-seq; Complex; Computational Science; Computer Models; Congenital Abnormality; Data; Data Science; Data Set; Databases; Defect; Dental; Dependence; Development; Development Plans; Ectoderm; Embryo; Enhancers; Face; FaceBase; Faculty; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Models; Genetic Transcription; Genome; Genomics; Goals; Growth; Histones; Human; Human Genetics; Instruction; Knowledge; Laboratories; Learning; Live Birth; Machine Learning; Mentors; Mentorship; Mesenchymal; Mesenchyme; Methods; Molecular; Morphogenesis; Mus; Muscle; Mutant Strains Mice; National Institute of Dental and Craniofacial Research; Oral; Pathology; Pattern; Performance; Population; Positioning Attribute; Process; Proteins; Regulatory Element; Research; Resources; Scientist; Signal Pathway; Signal Transduction; Solid; Study models; System; Techniques; Technology; Time; Tissues; Transcriptional Regulation; Transgenic Organisms; Validation; Wild Type Mouse; base; bone; career; career development; cell type; craniofacial; craniofacial development; critical period; design; differential expression; in silico; interest; medical specialties; mouse model; multiple omics; network models; next generation; orofacial cleft; programs; promoter; public database; recruit; research and development; single-cell RNA sequencing; spatiotemporal; tenure track; transcription factor; transcription regulatory network; transcriptome; transcriptome sequencing

Abstract Human craniofacial development is a complex process and frequently goes awry to cause a major class of birth defects, orofacial clefting, which affects approximately 1 in 700 live births. Proper facial development in mouse and human requires three sets of paired facial prominences coming together by growth, morphogenesis, and fusion. Embryonic facial development is strikingly similar in human and mouse, making the mouse the best available model system for human. Previous studies have shown that the expression of many thousands of genes changes across tissue layer, age, and/or prominence, as well as cell population during early mouse facial development. However, we still only have a rudimentary understanding of how these changes are regulated by the interaction of transcriptional modulators in the developing face. To understand how genes are transcriptionally regulated during facial development, this research seeks to construct transcriptional regulatory networks in a temporospatial manner by in silico analysis of publicly available multi- omic datasets. Aim 1 will focus on the identification and verification of transcriptional regulatory networks operating in facial mesenchyme with a focus on super-enhancers. Aim 2 will adopt a similar approach to study the ectoderm which acts as a vital signaling center for the mesenchyme. Finally, in Aim 3 I will apply knowledge from Aims 1 and 2 to build transcriptional regulatory networks at the single cell level. These aims will take advantage of available RNA-seq, ATAC-seq, histone marker ChIP-seq, transcription factor ChIP-seq, bulk and single cell RNA-seq data from wild-type or mutant mice, as well as facial enhancer expression databases. Accomplishment of these studies will predict how genes are transcriptionally regulated in a temporospatial manner during facial development and discover sets of core transcription factors and super- enhancers controlling facial development. These transcriptional regulatory networks will be relevant to the genetic and molecular underpinnings of human orofacial clefting, and will provide clear testable predictions about transcription factor function and the consequences of aberrant expression. Performance and accomplishment of these Aims will also act as a major component of my career development plan, in which my goal is to obtain and independent tenure-track faculty position and serve as a mentor to the next generation of scientists. A major aspect of my career development plan is to build on my growing strength in bioinformatics by learning more advanced techniques in this specialty alongside new computational based approaches, such as machine learning. In this respect, my Aims and career development plan are aligned with a Notice of Special Interest (NOSI) of NIDCR in Supporting Dental, Oral, and Craniofacial Research Using Bioinformatic, Computational, and Data Science Approaches (NOT-DE-20-006) for which this application is targeted. I have recruited a mentorship team with specialties in craniofacial biology, bioinformatics, machine learning, and career development to help me achieve these goals.

摘要 人类颅面发育是一个复杂的过程，经常出错，导致一个主要的类别， 出生缺陷，口面裂，影响到大约700个活产婴儿中的1个。适当的面部发育， 老鼠和人类需要三组成对的面部特征通过生长结合在一起， 形态发生和融合。人类和老鼠的胚胎面部发育惊人地相似， 小鼠是人类最好的模型系统。先前的研究表明， 成千上万的基因在组织层、年龄和/或显著性以及细胞群体中发生变化 在小鼠面部发育的早期然而，我们仍然只有一个初步的了解， 这些变化是由发育中的转录调节因子的相互作用调节的。了解 基因在面部发育过程中是如何转录调控的，这项研究旨在构建 转录调控网络在时空的方式，通过在硅片上分析公开可用的多， omic数据集AIM 1将集中于转录调控网络的识别和验证 在面部间充质中进行手术，重点是超级增强剂。目标2将采用类似的方法进行研究 外胚层是间充质的重要信号中心。最后，在目标3中，我将应用 目的1和2的知识，以建立单细胞水平的转录调控网络。这些目标 将利用可用的RNA-seq、ATAC-seq、组蛋白标记物ChIP-seq、转录因子ChIP-seq， 来自野生型或突变小鼠的批量和单细胞RNA-seq数据，以及面部增强子表达 数据库。这些研究的完成将预测基因是如何在转录调控中发挥作用的。 时空的方式在面部发育和发现套核心转录因子和超 控制面部发育的增强剂。这些转录调控网络将与 人类口面裂的遗传和分子基础，并将提供明确的可测试的预测 关于转录因子的功能和异常表达的后果。性能和 这些目标的实现也将作为我职业发展计划的一个重要组成部分，其中， 目标是获得独立的终身教职，并作为下一代的导师 科学家我的职业发展计划的一个主要方面是建立在我在生物信息学方面不断增长的实力 通过学习更先进的技术，在这个专业与新的计算为基础的方法，如 as machine机器learning学习.在这方面，我的目标和职业发展计划与 特别兴趣（NOSI）的NIDCR在支持牙科，口腔和颅面研究使用生物信息学， 计算和数据科学方法（NOT-DE-20-006）。我有 招募了一个具有颅面生物学、生物信息学、机器学习和 职业发展，帮助我实现这些目标。