Open AccessFolate Receptor Alpha Upregulates Oct4 , Sox2 and Klf4 and Downregulates miR‐138 and miR‐let‐7 in Cranial Neural Crest Cells
Author(s) -
Mohanty Vineet,
Shah Amar,
Allender Elise,
Siddiqui M. Rizwan,
Monick Sarah,
Ichi Shunsuke,
ManiaFarnell Barbara,
G. McLone David,
Tomita Tadanori,
Mayanil Chandra Shekhar
Publication year - 2016
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2421
Subject(s) - biology , sox2 , neural crest , chromatin immunoprecipitation , klf4 , microbiology and biotechnology , psychological repression , transcription factor , gene , genetics , promoter , gene expression , embryo
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