Nucleic acid methylation and orofacial morphogenesis

Abstract

In this review, we highlight the current state of knowledge of the diverse roles nucleic acid methylation plays in the embryonic development of the orofacial region and how aberrant methylation may contribute to orofacial clefts. We also consider the role of methylation in the regulation of neural crest cell function as it pertains to orofacial ontogeny. Changes in DNA methylation, as a consequence of environmental effects, have been observed in the regulatory regions of several genes, potentially identifying new candidate genes for orofacial clefting and opening promising new avenues for further research. While the focus of this review is primarily on the nonsyndromic forms of orofacial clefting, syndromic forms are briefly discussed in the context of aberrant nucleic acid methylation. K E Y W O R D Sbirth defects, epigenetics, neural crest cells, nucleic acid methylation, orofacial clefts

Role of epigenetics and miRNAs in orofacial clefts

“…At the organismal and cellular levels, environmental factors influence epigenetic modifications in ways that can lead to altered developmental outcomes (Feil & Fraga, 2012). Many cases of non‐syndromic OFCs, including CL/P and CPO, are suspected to be the result of G×E interactions (Dixon et al, 2011; Jambhekar, Dhall, & Shi, 2019; Seelan et al, 2019). Epigenetic modification could therefore explain, at least partly, variability of OFC prevalence between human populations that are otherwise not explained by genotypic differences.…”

“…Environmental factors, particularly folates and retinoids, are considered where relevant toward understanding the role of epigenetics in OFCs. Due to space constraints, we refer readers to another review for the role of genomic imprinting on OFCs (Seelan et al, 2019). Other environmental mechanisms contributing to OFCs are examined in greater detail in a companion review (Garland et al, in this issue).…”

“…C‐methylation (methylation from here on) is catalyzed by DNA methyltransferases (DNMTs) which rely solely on the pool of S‐adenosylmethionine (SAM) to supply methyl groups (Lei et al, 1996). Consequently, the methyltransferase activities of DNMTs (as well as histone‐modifying enzymes) are dependent on adequate SAM generated by the folate and methionine cycles (Seelan et al, 2019).…”

“…In a review of nucleic acid methylation and orofacial development, Seelan et al (2019) briefly discuss the possible role for A‐methylation in RNA (Seelan et al, 2019). RNA modifications typically involve N 6 mA methylations mediated by six members of the Nsun family of genes ( Nsun2 through Nsun7 ) that contain the NOL1/NOP2/sun domain (Chi & Delgado‐Olguin, 2013; Yue, Liu, & He, 2015).…”

“…In particular, these may explain previously observed inconsistencies and divergent findings (Schoen et al, 2017; Sharp et al, 2017). Furthermore, some of these mechanisms are known to be influenced by environmental factors (Seelan, Pisano, & Greene, 2019; Garland et al, in this issue). In this review, we summarize the current standing of the field regarding epigenetic and microRNA‐related mechanisms of OFCs.…”