DNA methylation in orofacial clefting

口颌面裂中的 DNA 甲基化

基本信息

批准号：
10636261
负责人：
Robert Lipinski
金额：
$ 47.31万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636261
关键词：
Address Advanced Development Affect Attenuated Biological Biological Models Biology Cell Differentiation process Cell Proliferation Cell physiology Cells Cephalic Chemicals Choline Complex Conceptions Congenital Abnormality Connective Tissue DNA Methylation DNA Methylation Inhibition Data Development Dietary intake Embryo Environment Epidemiology Epigenetic Process Etiology Face Folic Acid Foundations Gene Expression Genetic Genetic Models Genetic Transcription Genetic study Genome Goals Head Human Individual Intervention Investigation Knowledge Link Lip structure Mediating Mediator Medical Methylation Modeling Molecular Morbidity - disease rate Morphogenesis Multipotent Stem Cells Neural Crest Neural Crest Cell Newborn Infant Outcome Palate Pathogenesis Penetrance Play Population Predisposition Prevention Prevention strategy Proliferating Reporting Research Risk Risk Reduction Role Structural Congenital Anomalies Structural defect Testing Therapeutic Tissues antagonist cleft lip and palate comparison control craniofacial dietary epigenome editing genome wide methylation in vitro Model in vivo insight malformation methylome mouse model novel orofacial orofacial cleft orofacial development prevent response stem cell population trait transcriptome transcriptome sequencing transcriptomics whole genome

项目摘要

Understanding the role of malleable epigenetic mechanisms in birth defects is a direct path to prevention strategies. Orofacial clefts (OFCs) of the lip and palate are among the most common human structural birth defects, affecting 1 in 800 newborns, and pose serious individual, familial, and societal burdens. Prevention strategies for OFCs are elusive because our current understanding of causative factors is inadequate. Epidemiologic and traditional genetic studies have shown that OFCs are etiologically complex outcomes that result from multifactorial genetic and environmental influences. Epigenetic mechanisms are an exciting new focus in understanding the genesis of OFCs because they mediate the effect of environmental influences on the genome during sensitive embryonic periods. Our proposal specifically focuses on DNA methylation because this epigenetic mechanism is environmentally sensitive and a practical target of prevention and therapeutic strategies. While implicated by multiple lines of evidence, the biological role of DNA methylation in orofacial development is unclear. We have established novel models and generated key proofs of concepts that poise us to uncover how DNA methylation regulates orofacial morphogenesis and to define the role that DNA methylation plays in modulating OFC susceptibility. In this project, integrated genome-wide methylation and bulk and single-cell transcriptome approaches will be applied to define molecular and cellular mechanisms of OFC pathogenesis resulting from disrupted DNA methylation in the cranial neural crest. The role of DNA methylation in multifactorial OFC susceptibility will then be defined by integrating multiple environmental and dietary modulators of DNA methylation to genetic (Wnt9b KO) and chemical (Shh antagonist) mouse models of incompletely penetrant OFCs. Finally, epigenome editing will be applied to evaluate the functional impact of OFC-associated methylation changes on gene expression and cranial neural crest biology. Completion of the proposed studies will bring fundamental insight into how DNA methylation regulates cranial neural crest biology and orofacial morphogenesis. By defining environmental- and dietary-mediated methylome- transcriptome responses that alter OFC susceptibility, these studies will also provide a necessary foundation for identification of environmental influences that modulate DNA methylation and contribute to OFC risk. Pursuing this line of investigation will advance our long-term goal of developing prevention strategies for etiologically complex birth defects by identifying culpable environmental influences and defining their mechanisms of action.

了解可延展的表观遗传机制在先天缺陷中的作用是预防的直接途径策略。嘴唇和口感的口面裂（OFC）是最常见的人类结构性出生缺陷，影响了800名新生儿中有1个，并构成了严重的个人，家族和社会负担。预防 OFC的策略难以捉摸，因为我们目前对因果因素的理解不足。流行病学和传统遗传研究表明，OFC是病因学上的复杂结果，由多因素遗传和环境影响产生。表观遗传机制是一种令人兴奋的新专注于理解OFC的起源，因为它们介导了环境影响的影响敏感胚胎时期的基因组。我们的建议特别关注DNA甲基化，因为这种表观遗传机制对环境敏感，是预防和治疗的实用目标策略。虽然由多种证据与DNA甲基化的生物学作用有关发展尚不清楚。我们已经建立了新颖的模型并产生了使我们有利的概念的关键证据揭示DNA甲基化如何调节口面形态发生并定义DNA的作用甲基化在调节易感性的调节中起作用。在这个项目中，全基因组甲基化和批量和单细胞转录组方法将应用于定义分子和细胞机制 OFC发病机理是由颅神经rest中DNA甲基化中断引起的。 DNA的作用然后，将通过整合多个环境和 DNA甲基化对遗传（WNT9B KO）和化学（SHH拮抗剂）小鼠模型的饮食调节剂不完全渗透的OFC。最后，将应用表观基因组编辑来评估 OFC相关的甲基化基因表达和颅神经rest生物学的变化。完成拟议的研究将对DNA甲基化如何调节颅神经crest带来基本见解生物学和口面形态发生。通过定义环境和饮食介导的甲基团转录组响应改变了OFC易感性，这些研究还将为识别调节DNA甲基化并导致OFC风险的环境影响。进行这一调查将促进我们制定预防策略的长期目标通过识别可屈服的环境影响并定义其病因复杂的出生缺陷作用机理。