DNA Methylation in Orofacial Clefting

唇腭裂(OFC)是常见的结构性出生缺陷，每700名新生儿中就有1名受到影响。 这些畸形会导致严重的发病率，需要广泛的医疗干预，并造成严重的 个人、家庭和社会负担。患有OFCS的儿童平均接受6次手术，身体健康 护理费用比同龄人高800%，而且在生命的各个阶段都有更高的死亡率。预防 离岸金融中心的战略是难以捉摸的，因为我们目前对致病因素的了解还不充分。 流行病学和传统遗传学研究表明，OFC是病因复杂的特征，可能 是基因-环境相互作用的结果。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。这个应用程序特别关注DNA甲基化，因为 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 发展情况尚不清楚。此外，虽然许多与口腔发育有关的分子介质已经被 确定在唇裂发病过程中受DNA甲基化调控的特定基因和途径 还没有得到很好的定义。本申请中提出的研究利用了遗传学和药理学。 确定DNA甲基化在口腔面部发育和全基因组中的生物学作用的方法 DNA甲基化和转录表达的综合分析以确定候选基因和 对甲基化变化敏感的途径。这些目标的实现将使这一领域向前推进 极大地提高了我们对DNA甲基化调节的基本机制的理解 面部发育，以及这一关键表观遗传过程的调节如何导致OFCS。结果是 预计将把这种对环境敏感的机制与不同的生物过程和细胞种群联系起来， 并确定一组受表观遗传调控和环境敏感的目标。这将是 为未来的重点研究工作奠定基础，这些工作将推进我们的长期目标 病因复杂的出生缺陷的预防策略。

Orofacial clefts (OFCs) of the lip and palate are common structural birth defects, affecting 1 in 700 newborns. These malformations cause significant morbidity, require extensive medical intervention, and pose serious individual, familial, and societal burdens. Children with OFCs undergo an average of six surgeries, have health care costs 800% greater than their peers, and have higher mortality rates at all stages of life. 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 traits that likely result from gene-environment interactions. 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 application 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 not known. Moreover, while many molecular mediators of orofacial development have been identified, the specific genes and pathways that are regulated by DNA methylation during cleft pathogenesis have not been well defined. The studies proposed in this application utilize genetic and pharmacologic approaches to define the biological role of DNA methylation in orofacial development, and genome-wide integrative analysis of DNA methylation and transcriptional expression to identify candidate genes and pathways that are sensitive to changes in methylation. Completion of these Aims will advance the field by dramatically increasing our understanding of the basic mechanisms by which DNA methylation regulates orofacial development, and how modulation of this key epigenetic process results in OFCs. The results are expected to link this environmentally-sensitive mechanism to a distinct biological process and cell population, and identify a focused group of epigenetically-regulated and environmentally-sensitive targets. This will provide a foundation for future focused research efforts that will advance our long term goal of developing prevention strategies for etiologically complex birth defects.