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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：
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