AbstractNon-syndromic cleft lip/palate (NSCLP), the most common human craniofacial malformations, is a complex disorder given its genetic heterogeneity and multifactorial component revealed by genetic, epidemiological and epigenetic findings. Association of epigenetic variations with NSCLP has been made, however still of little functional investigation. Here we combined a reanalysis of NSCLP methylome data with genetic analysis and used both in vitro and in vivo approaches to dissect the functional effects of epigenetic changes. We found a frequent differentially methylated region in mir152, hypomethylated in NSCLP cohorts (21-26%), leading to mir152 overexpression. In vivo analysis using zebrafish embryos revealed that mir152 upregulation leads to craniofacial impairment analogue to palatal defects. Also, we demonstrated that zebrafish embryonic hypoxia leads to mir152 upregulation combined with mir152 hypomethylation and also analogue palatal alterations. We therefore suggest mir152 hypomethylation, potentially induced by hypoxia in early development, as a novel and frequent predisposing factor to NSCLP.
Central nervous system and craniofacial malformations. Vol. 7 in advances in the study of birth defects. T.V.N. Persaud (ed.) Alan R. Liss, Inc., New York, 1982, 181 pp., $32
