“mir152 hypomethylation, potentially triggered by embryonic hypoxia, as a common mechanism for non-syndromic cleft lip/palate”

Non-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 and approaches to dissect the functional effects of epigenetic changes. We found a frequent differentially methylated region in , hypomethylated in NSCLP cohorts (21-26%), leading to overexpression. analysis using zebrafish embryos revealed that upregulation leads to craniofacial impairment analogue to palatal defects. Also, we demonstrated that zebrafish embryonic hypoxia leads to upregulation combined with hypomethylation and also analogue palatal alterations. We therefore suggest hypomethylation, potentially induced by hypoxia in early development, as a novel and frequent predisposing factor to NSCLP.