Young Juan I, Slifer Susan, Hecht Jacqueline T, Blanton Susan H
John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, United States.
McGovern Medical School, University of Texas Health Science Center, Houston, TX, United States.
Front Cell Dev Biol. 2021 May 12;9:656865. doi: 10.3389/fcell.2021.656865. eCollection 2021.
Non-syndromic cleft lip with or without cleft palate (NSCLP) is the most common craniofacial birth defect. The etiology of NSCLP is complex with multiple genes and environmental factors playing causal roles. Although studies have identified numerous genetic markers associated with NSCLP, the role of epigenetic variation remains relatively unexplored. Because of their identical DNA sequences, monozygotic (MZ) twins discordant for NSCLP are an ideal model for examining the potential contribution of DNA methylation to non-syndromic orofacial clefting. In this study, we compared the patterns of whole genome DNA methylation in six MZ twin pairs discordant for NSCLP. Differentially methylated positions (DMPs) and regions (DMRs) were identified in NSCLP candidate genes, including differential methylation in and in two independent MZ twin pairs. In addition to DNA methylation differences in NSCLP candidate genes, we found common differential methylation in genes belonging to the Hippo signaling pathway, implicating this mechanosensory pathway in the etiology of NSCLP. The results of this novel approach using MZ twins discordant for NSCLP suggests that differential methylation is one mechanism contributing to NSCLP, meriting future studies on the role of DNA methylation in familial and sporadic NSCLP.
非综合征性唇裂伴或不伴腭裂（NSCLP）是最常见的颅面先天性缺陷。NSCLP的病因复杂，多种基因和环境因素都起到了致病作用。尽管研究已经确定了许多与NSCLP相关的遗传标记，但表观遗传变异的作用仍相对未被探索。由于同卵双胞胎（MZ）的DNA序列相同，因此患有NSCLP的不一致同卵双胞胎是研究DNA甲基化对非综合征性口面部裂隙形成潜在贡献的理想模型。在本研究中，我们比较了六对患有NSCLP的不一致同卵双胞胎的全基因组DNA甲基化模式。在NSCLP候选基因中鉴定出了差异甲基化位点（DMP）和区域（DMR），包括在两对独立的同卵双胞胎中的 和 的差异甲基化。除了NSCLP候选基因中的DNA甲基化差异外，我们还在属于Hippo信号通路的基因中发现了常见的差异甲基化，这表明该机械感觉通路在NSCLP的病因学中起作用。这项使用患有NSCLP的不一致同卵双胞胎的新方法的结果表明，差异甲基化是导致NSCLP的一种机制，值得未来对DNA甲基化在家族性和散发性NSCLP中的作用进行研究。
