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. ? ? ?
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