Alterations in DNA Methylation in Orofacial Clefts

Abstract

Orofacial clefts are among the most common craniofacial anomalies with multifactorial etiologies, including genetics and environments. DNA methylation, one of the most acknowledged mechanisms of epigenetics, is involved in the development of orofacial clefts. DNA methylation has been examined in patients with non-syndromic cleft lip with cleft palate (nsCL/P) from multiple specimens, including blood, saliva, lip, and palate, as well as experimental studies in mice. The results can be reported in two different trends: hypomethylation and hypermethylation. Both hypomethylation and hypermethylation can potentially increase the risk of nsCL/P depending on the types of specimens and the specific regions on each gene and chromosome. This is the most up-to-date review, intending to summarize evidence of the alterations of DNA methylation in association with the occurrence of orofacial clefts. To make things straightforward to understand, we have systematically categorized the data into four main groups: human blood, human tissues, animal models, and the factors associated with DNA methylation. With this review, we are moving closer to the core of DNA methylation associated with nsCL/P development; we hope this is the initial step to find a genetic tool for early detection and prevention of the occurrence of nsCL/P.

Predisposing factors of non‐syndromic cleft lip and cleft palate in the northern Thai population: A 10‐year retrospective case–control study

“…Mukhopadhyay et al 30 performed a study in mice models with cigarette smoke extract application, which showed a significant decrease in global DNA methylation of the first branchial arch cell (an embryologic precursor of lip and palatal cell), resulting in CL/P. 31 Another mechanism is fetal hypoxia due to decreasing maternal-fetal blood circulation by the effect of nicotine-induced vasoconstriction. 32,33 Previous studies demonstrated the association between the risk of orofacial cleft and maternal consumption of caffeinated beverages.…”

“…Fetal hyperhomocysteinemia can cause disruption of DNA methylation resulting in hypomethylation and increased risk of CL/P. 31 Another possible mechanism is iron deficiency due to caffeine-inhibiting iron absorption. 38 Iron is one of the protective factors of CL/P.…”

“…A recent study by Lammer et al 29 reported the biotransformation of toxic substances in tobacco, aromatic amine, induced polymorphic gene variation of fetal acetyl‐N‐transferases 1 (NAT1) and 2 (NAT2), which is associated with the risk of CL/P. Mukhopadhyay et al 30 performed a study in mice models with cigarette smoke extract application, which showed a significant decrease in global DNA methylation of the first branchial arch cell (an embryologic precursor of lip and palatal cell), resulting in CL/P 31 . Another mechanism is fetal hypoxia due to decreasing maternal–fetal blood circulation by the effect of nicotine‐induced vasoconstriction 32,33 …”

“…Homocysteine is an intermediate product in the cystine/methionine cycle. Fetal hyperhomocysteinemia can cause disruption of DNA methylation resulting in hypomethylation and increased risk of CL/P 31 . Another possible mechanism is iron deficiency due to caffeine‐inhibiting iron absorption 38 .…”