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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE018215-02
Application #
7667484
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2008-08-01
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$333,000
Indirect Cost
Name
University of Louisville
Department
Dentistry
Type
Schools of Dentistry
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Seelan, Ratnam S; Mukhopadhyay, Partha; Warner, Dennis R et al. (2017) Determinants of orofacial clefting II: Effects of 5-Aza-2'-deoxycytidine on gene methylation during development of the first branchial arch. Reprod Toxicol 67:100-110
Mukhopadhyay, Partha; Seelan, Ratnam S; Rezzoug, Francine et al. (2017) Determinants of orofacial clefting I: Effects of 5-Aza-2'-deoxycytidine on cellular processes and gene expression during development of the first branchial arch. Reprod Toxicol 67:85-99
Warner, Dennis R; Smith, Scott C; Smolenkova, Irina A et al. (2016) Inhibition of p300 histone acetyltransferase activity in palate mesenchyme cells attenuates Wnt signaling via aberrant E-cadherin expression. Exp Cell Res 342:32-8
Warner, Dennis; Ding, Jixiang; Mukhopadhyay, Partha et al. (2015) Temporal Expression of miRNAs in Laser Capture Microdissected Palate Medial Edge Epithelium from Tgf?3(-/-) Mouse Fetuses. Microrna 4:64-71
Mukhopadhyay, Partha; Greene, Robert M; Pisano, M Michele (2015) Cigarette smoke induces proteasomal-mediated degradation of DNA methyltransferases and methyl CpG-/CpG domain-binding proteins in embryonic orofacial cells. Reprod Toxicol 58:140-8
Warner, Dennis R; Mukhopadhyay, Partha; Brock, Guy et al. (2014) MicroRNA expression profiling of the developing murine upper lip. Dev Growth Differ 56:434-47
Seelan, Ratnam S; Mukhopadhyay, Partha; Warner, Dennis R et al. (2014) Methylated microRNA genes of the developing murine palate. Microrna 3:160-73
Jin, Jiu-Zhen; Warner, Dennis R; Lu, Qingxian et al. (2014) Deciphering TGF-?3 function in medial edge epithelium specification and fusion during mouse secondary palate development. Dev Dyn 243:1536-43
Seelan, Ratnam S; Appana, Savitri N; Mukhopadhyay, Partha et al. (2013) Developmental profiles of the murine palatal methylome. Birth Defects Res A Clin Mol Teratol 97:171-86
Warner, Dennis R; Wells, Justin P; Greene, Robert M et al. (2013) Gene expression changes in the secondary palate and mandible of Prdm16(-/-) mice. Cell Tissue Res 351:445-52

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