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Background  Cleft palate (CP) is the second most common congenital birth defect; however, the relationship between CP-associated genes and epigenetic regulation remains largely unknown. In this study, we investigated the contribution of microRNAs (miRNAs) to cell proliferation and regulation of genes involved in CP development.    Methods  In order to identify all genes for which mutations or association/linkage have been found in individuals with CP, we conducted a systematic literature search, followed by bioinformatics analyses for these genes. We validated the bioinformatics results experimentally by conducting cell proliferation assays and miRNA-gene regulatory analyses in cultured human palatal mesenchymal cells treated with each miRNA mimic.    Results  We identified 131 CP-associated genes in the systematic review. The bioinformatics analysis indicated that the CP genes were associated with signaling pathways, microRNAs (miRNAs), metabolic pathways, and cell proliferation. A total 17 miRNAs were recognized as potential modifiers of human CP genes. To validate miRNA function in cell proliferation, a main cause of CP, we conducted cell proliferation/viability assays for the top 11 candidate miRNAs from our bioinformatics analysis. Overexpression of miR-133b, miR-374a-5p, and miR-4680-3p resulted in a more than 30% reduction in cell proliferation activity in human palatal mesenchymal cell cultures. We found that several downstream target CP genes predicted by the bioinformatics analyses were significantly downregulated through induction of these miRNAs ( FGFR1 ,  GCH1 ,  PAX7 ,  SMC2 , and  SUMO1  by miR-133b;  ARNT ,  BMP2 ,  CRISPLD1 ,  FGFR2 ,  JARID2 ,  MSX1 ,  NOG ,  RHPN2 ,  RUNX2 ,  WNT5A  and  ZNF236  by miR - 374a-5p; and  ERBB2 ,  JADE1 ,  MTHFD1  and  WNT5A  by miR-4680-3p) in cultured cells.    Conclusions  Our results indicate that miR-374a-5p, miR-4680-3p, and miR-133b regulate expression of genes that are involved in the etiology of human CP, providing insight into the association between CP-associated genes and potential targets of miRNAs in palate development.    Electronic supplementary material  The online version of this article (10.1186/s12920-019-0546-z) contains supplementary material, which is available to authorized users.

bmc medical genomics

MicroRNA-374a, -4680, and -133b suppress cell proliferation through the regulation of genes associated with human cleft palate in cultured human palate cells