NUTRITIONAL EPIGENETICS AND OROFACIAL DEVELOPMENT

描述（由申请人提供）：两个主要的卫生保健问题是不可阻挡地交织在一起的：一个女人的健康，和她未出生的孩子的产前发育。女性饮食的营养价值对两者都至关重要。叶酸是一种水溶性的B族维生素，是胎儿组织生长、中枢神经系统和口面复合体正常发育所必需的。此外，叶酸为DNA甲基化提供必要的甲基供体，DNA甲基化是调节哺乳动物细胞中基因表达的最常见的表观遗传修饰之一。不正确的甲基化模式可导致发育畸形，包括颅面缺陷。虽然DNA的甲基化是一种常见的表观遗传修饰，有助于控制哺乳动物细胞中的基因表达，但离散CpG岛的组织/细胞特异性甲基化的概念作为调节口面区域形态发生的手段，并且作为本发明中概述的营养（叶酸）缺乏的分子靶点是新颖的。因此，我们计划在当前提案中解决的全局假设是，叶酸缺乏可以破坏特定候选基因的正常甲基化状态，并有助于口面裂的发展。 本申请中提出的具体目标/假设包括： 在第一鳃弓的个体发育过程中，具有组织依赖性和差异甲基化区域（t-dmrs）的1 - CpG岛表现出不同的时空甲基化模式。 2 -妊娠期叶酸缺乏导致面裂的情况，引起第一鳃弓中CpG岛甲基化模式的改变。这些模式可以通过叶酸补充方案逆转，以挽救表型。 3 -改变的启动子CpG甲基化模式调节叶酸缺乏（Folbp 1-/-）小鼠胚胎第一鳃弓中TGF（信号转导家族）基因的表达。 4 -叶酸缺乏（Folbp 1-/-）通过诱导发育中的第一鳃弓内的过量细胞凋亡而导致口面裂的发生。

DESCRIPTION (provided by applicant): Two Two major health care issues are inexorably intertwined: a woman's health, and prenatal development of her unborn child. The nutritional value of a woman's diet is critical to both. Folate, a water- soluble B vitamin, is required for the growth of fetal tissues, and normal development of the CNS and orofacial complex. In addition, folate supplies the necessary methyl donors for DNA methylation, one of the most common epigenetic modifications regulating gene expression in mammalian cells. Incorrect methylation patterns can result in developmental malformations including craniofacial defects. With a frequency of 1-2 in 1,000 live births, orofacial clefts represent nearly one-half of all craniofacial anomalies, While methylation of DNA is a common epigenetic modification that contributes to the control of gene expression in mammalian cells, the notion of tissue/cell-specific methylation of discrete CpG islands as a means of regulating morphogenesis of the orofacial region, and as a molecular target of nutritional (folate) deficiency as outlined in the present proposal is novel. Thus, the global hypothesis we plan to address in the current proposal is that folate deficiency can disrupt the normal methylation state of specific candidate genes and contribute to development of orofacial clefts. Specific aims/hypotheses addressed in the current application include: 1 - CpG islands, with tissue-dependent and differentially methylated regions (t-dmrs), exhibit distinct spatio- temporal methylation patterns during ontogeny of the 1st branchial arch. 2 - Conditions of gestational folate deficiency that result in facial clefts, elicit alterations in CpG island methylation patterns in the 1st branchial arch. These patterns can be reversed with folate supplementation regimens that rescue the phenotype. 3 - Altered promoter CpG methylation patterns regulate expression of genes of the TGF( Signal Transduction Family in the embryonic 1st branchial arch from folate deficient (Folbp1-/-) mice. 4 - Folate deficiency (Folbp1-/-) contributes to the genesis of orofacial clefts by inducing excess apoptosis within the developing 1st branchial arch.