Integrated multi-omics analyses of early mammalian craniofacial development

早期哺乳动物颅面发育的综合多组学分析

基本信息

批准号：
9891599
负责人：
Justin Lee Cotney
金额：
$ 16.4万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-08 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891599
关键词：
Address Affect Architecture Biological Biology Body part Cephalic Characteristics Child Chromatin Chromatin Interaction Analysis by Paired-End Tag Sequencing Code Complex Congenital Abnormality Coupled Craniofacial Abnormalities Craniosynostosis Data Data Set Defect Development Disease Embryo Embryonic Development Enhancers Exons Expression Profiling Face FaceBase Gene Expression Gene Expression Regulation Genes Genetic Genome Heritability Human Immunoprecipitation Incidence Individual Laboratories Ligation Link Live Birth Machine Learning Measures Modeling Mus Mutation Network-based Neural Crest Cell Nucleic Acid Regulatory Sequences Organ Organism Pathway Analysis Pathway interactions Pattern Play Pregnancy Process Proteins RNA Regulator Genes Regulatory Element Role Sampling Series Signal Transduction Specificity Syndrome TWIST1 gene Testing Time Tissue Sample Tissues Work base comparative computational pipelines craniofacial craniofacial development differential expression embryo tissue epigenome epigenomics exome sequencing falls gene interaction genetic information genome wide association study human tissue multiple omics orofacial orofacial cleft programs promoter transcriptome transcriptomics virtual whole genome

项目摘要

Abstract Craniofacial abnormalities are some of the most commonly occurring human birth defects worldwide, with up to 200,000 children born every year with some type of craniofacial defect. These defects can occur as part of complex syndromes that involve multiple tissues and organs. The syndromic forms of these disorders have been successfully linked to nearly 500 genes including TWIST1 for craniosynostosis and IRF6 for orofacial clefting. However more frequently no other part of the body is directly involved (50% of craniosynostoses, 70% of orofacial clefts). Genome wide association studies indicate heritability for such defects, however the vast majority of associations fall outside of genes suggesting defective gene regulation is a major contributor to incidence of such defects. Gene regulatory elements can be located throughout the genome and typically have tissue-specific activity, making them difficult to identify and predict what gene they control. The overall objective of this application is to integrate epigenomic and transcriptomic data sets from early human and mouse craniofacial development from our lab as well as FaceBase to comprehensively predict regulatory element-gene interactions. Our hypothesis posits that conserved regulatory networks between human and mouse are enriched for disease relevant biology. In Aim 1 we propose to systematically identify chromatin states in human from 4.5 to 8 weeks of gestation and in mouse from embryonic days 9.5 to 15.5. In Aim 2 we propose to identify genes that are coordinately regulated in both species across these developmental windows. Finally, in Aim 3 we propose to integrate these two disparate network types to identify regulatory element-gene pairings. We will experimentally validate predicted interactions in a culture model of cranial neural crest cells using proximity-ligation coupled with immunoprecipitation. Our proposed studies will generate the most comprehensive epigenomic and transcriptomic networks in a developing human tissue and for the first time identify the conserved regulatory architecture for building the mammalian orofacial complex.

抽象的颅面异常是全世界最常见的人类出生缺陷，每年出生多达200,000个儿童，患有某种类型的颅面缺陷。这些缺陷可以作为涉及多个组织和器官的复杂综合征的一部分。综合征的形式这些疾病已成功链接到近500个基因，包括Twist1 颅骨突变和IRF6用于口面裂。但是，更频繁地没有身体的其他部位直接涉及（50％的颅内突出sos剂，占口腔裂缝的70％）。基因组广泛的研究表明这种缺陷的遗传力，但是绝大多数关联属于基因之外提示缺陷的基因调节是导致此类缺陷发生率的主要因素。基因调节元素可以位于整个基因组中，通常具有组织特异性活性，使他们难以识别和预测他们控制的基因。总体目标应用是为了整合早期人和小鼠的表观基因组和转录组数据集从我们的实验室和面库中进行颅面发展，以全面预测调节元素 - 基因相互作用。我们的假设假设了保守的监管网络人和小鼠富含有关疾病相关的生物学。在目标1中，我们建议系统地鉴定人类在妊娠4.5周至8周内的染色质状态以及从胚胎第9.5至15.5天。在AIM 2中，我们建议确定在这两个物种都遍布这些发育窗口。最后，在目标3中，我们建议将这两个集成不同的网络类型以识别法规元素 - 基因配对。我们将通过实验验证在颅神经rest细胞的培养模型中，使用接近结合耦合的预测相互作用免疫沉淀。我们提出的研究将产生最全面的表观基因组学和发展中的人体组织中的转录组网络，并首次确定保守的用于建造哺乳动物口面综合体的监管结构。