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DNA methylation in orofacial clefting

口颌面裂中的 DNA 甲基化

基本信息

批准号：
10667252
负责人：
Robert Lipinski
金额：
$ 43.84万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-03 至 2024-08-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10667252
关键词：
Address Advanced Development Affect Attenuated Biological Biological Models Biology Cell Differentiation process Cell Proliferation Cell physiology Cells Cephalic Chemicals Choline Complex Congenital Abnormality Connective Tissue DNA Methylation DNA Methylation Inhibition Data Development Dietary intake Embryo Epidemiology Epigenetic Process Etiology Event Face Folic Acid Foundations Future Genetic Genetic Models Genetic study Genome Goals Head Human Individual Intervention Investigation Knowledge Link Lip structure Mediating 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 Reporting Research Risk Role Structural Congenital Anomalies Structural defect Supplementation Testing Therapeutic Tissues Work antagonist cleft lip and palate craniofacial dietary epigenomics genome wide methylation in vitro Model in vivo insight malformation methylome mouse model novel orofacial orofacial cleft orofacial development prevent response single cell sequencing stem cell population trait transcriptome transcriptomics

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 common human structural birth defects, affecting 1 in 800 newborns, that 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. This 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. We will apply integrated genome-wide methylation and bulk and single-cell transcriptome approaches to a novel mouse model in which OFCs result from disruption of DNA methylation in the cranial neural crest. We will also define the role of DNA methylation in multifactorial OFC susceptibility by integrating multiple environmental and dietary modulators of DNA methylation to genetic (Wnt9b KO) and chemical (Shh antagonist) mouse models of incompletely penetrant OFCs. Pursuit of the proposed studies will bring fundamental insight into how DNA methylation regulates cranial neural crest biology and orofacial morphogenesis and provide a critical foundation for future work interrogating the role of specific methylation events. Completion of these studies will also define environmental- and dietary-mediated methylome-transcriptome responses that alter OFC susceptibility and set the stage for definition of additional environmental influences that modulate DNA methylation and contribute to OFC risk. Pursing 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.

了解可塑性表观遗传机制在出生缺陷中的作用是预防出生缺陷的直接途径战略。唇腭裂是人类常见的结构性先天缺陷，影响1 在800名新生儿中，这构成了严重的个人、家庭和社会负担。离岸金融中心的预防策略是难以捉摸的，因为我们目前对致病因素的了解还不够充分。流行病学和传统的遗传学研究表明，OFC是由以下原因引起的复杂的结果多因素的遗传和环境影响。表观遗传机制是一个令人兴奋的新焦点了解OFCs的起源，因为它们介导了环境影响对基因组的影响在敏感的胚胎期。这项提议特别关注DNA甲基化，因为这表观遗传机制对环境敏感，是预防和治疗的实用靶点战略。虽然有多条证据表明，DNA甲基化在口腔面部的生物学作用事态发展尚不明朗。我们已经建立了新的模型，并生成了使我们保持镇定的概念的关键证据揭示DNA甲基化如何调节口腔面部形态发生，并确定DNA甲基化的作用甲基化在调节OFC易感性中起作用。我们将应用整合的全基因组甲基化和批量和单细胞转录组方法获得一种新的小鼠模型，在该模型中，OFCs由干扰脑神经脊区的DNA甲基化。我们还将定义DNA甲基化在多因素中的作用通过整合DNA甲基化的多种环境和饮食调节因子来提高OFC的易感性遗传性(Wnt9b KO)和化学(Shh拮抗剂)小鼠不完全穿透性OFCs模型。追求这项拟议的研究将为DNA甲基化如何调节脑神经脊带来根本性的洞察。生物学和口面部形态发生，并为今后的工作提供了关键的基础，审问特定的甲基化事件。这些研究的完成还将确定环境和饮食调节甲基组-转录组反应改变OFC的易感性并为定义额外的调节DNA甲基化并导致OFC风险的环境影响。追求这一行的这项研究将推进我们为病因复杂的分娩制定预防策略的长期目标通过确定应受责备的环境影响并定义其作用机制来确定缺陷。