Transcriptional Regulatory Networks of Craniofacial Development

颅面发育的转录调控网络

• 批准号: 10284443
• 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/10284443
• 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; recruit; research and development; single-cell RNA sequencing; spatiotemporal; tenure track; transcription factor; 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.

抽象的 人类颅面的发展是一个复杂的过程，经常出现大类造成一类主要的过程 出生缺陷，口面裂，影响700个活产中大约1个。适当的面部发展 小鼠和人类需要三组成对的面部突出，随着生长的增长而聚集在一起 形态发生和融合。胚胎面部发育在人和老鼠中非常相似，使 鼠标是人类最佳可用模型系统。先前的研究表明， 跨组织层，年龄和/或突出以及细胞种群的数千种基因变化 在老鼠早期的面部发育期间。但是，我们仍然只对这些 变化受发展面中转录调节器的相互作用的调节。理解 基因在面部发育过程中如何进行转录调节，该研究试图构建 通过暂时性空间的转录调节网络，通过对公共可用的多种 OMIC数据集。 AIM 1将重点介绍转录调节网络的识别和验证 在面部间充质中运行，重点是超级增强剂。 AIM 2将采用类似的学习方法 充当间充质的重要信号中心的外胚层。最后，在目标3中，我将申请 AIM 1和2的知识以在单个单元格级别构建转录调节网络。这些目标 将利用可用的RNA-seq，atac-seq，组蛋白标记芯片芯片，转录因子芯片seq， 来自野生型或突变小鼠的散装和单细胞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在A中的转录调节 面部发育期间的暂时性方式，发现核心转录因子和超级词 控制面部开发的增强剂。这些转录监管网络将与 人类口面裂基的遗传和分子基础，将提供明确的可测试预测 关于转录因子功能和异常表达的后果。性能和 这些目标的实现也将成为我职业发展计划的重要组成部分，我 目标是获得和独立的任期教师职位，并成为下一代的导师 科学家。我的职业发展计划的一个主要方面是建立我在生物信息学方面的增长 通过在这种专业中学习更先进的技术以及新的基于计算的方法， 作为机器学习。在这方面，我的目标和职业发展计划与 NIDCR的特殊兴趣（NOSI）在支持牙齿，口腔和颅面研究中使用生物信息学， 该应用程序针对的计算和数据科学方法（非DE-20-006）。我有 招募了一支具有颅面生物学，生物信息学，机器学习和的指导团队 职业发展可以帮助我实现这些目标。