NUTRITIONAL EPIGENETICS AND OROFACIAL DEVELOPMENT

描述（由申请人提供）：两个主要的卫生保健问题不可避免地交织在一起：妇女的健康和未出生孩子的产前发育。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甲基化提供了必要的甲基供体，这是哺乳动物细胞中调节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/细胞特异性甲基化作为调节口面部区域形态发生的一种手段，以及作为营养（叶酸）缺乏的分子靶点，这一概念在本提议中是新颖的。因此，我们计划在当前的提案中解决的全球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，并促进口面部裂的发展。

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.