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A bstract   Prenatal folic acid (FA) supplementation prevents neural tube defects. Folate receptor alpha (FRα) is critical for embryonic development, including neural crest (NC) development. Previously we showed that FRα translocates to the nucleus in response to FA, where it acts as a transcription factor. In this study, we examined if FA through interaction with FRα regulates stem cell characteristics of cranial neural crest cells (CNCCs)‐critical for normal development. We hypothesized that FRα upregulates coding genes and simultaneously downregulates non‐coding miRNA which targets coding genes in CNCCs. Quantitative RT‐PCR and chromatin immunoprecipitation showed that FRα upregulates  Oct4 ,  Sox2,  and  Klf4  by binding to their  cis ‐regulator elements‐5′ enhancer/promoters defined by H3K27Ac and p300 occupancy. FA via FRα downregulates miRNAs, miR‐138 and miR‐let‐7, which target  Oct4  and  Trim71  (an Oct4 downstream effector), respectively. Co‐immunoprecipitation data suggests that FRα interacts with the Drosha‐DGCR8 complex to affect pre‐miRNA processing. Transfecting anti‐miR‐138 or anti‐miR‐let‐7 into non‐proliferating neural crest cells (NCCs) derived from  Splotch  ( Sp  −/− ), restored their proliferation potential. In summary, these results suggest a novel pleiotropic role of FRα: (a) direct activation of  Oct4 ,  Sox2,  and  Klf4  genes; and (b) repression of biogenesis of miRNAs that target these genes or their effector molecules. S tem  C ells   2016;34:2721–2732

Folate Receptor Alpha Upregulates Oct4 , Sox2 and Klf4 and Downregulates miR‐138 and miR‐let‐7 in Cranial Neural Crest Cells