title: Folic acid stimulation of neural stem cell proliferation is associated with altered methylation profile of PI3K/Akt/CREB.
abstract: Proliferation of neural stem cells (NSCs) is required for development and repair in the nervous system. NSC amplification in vitro is a necessary step towards using NSC transplantation therapy to treat neurodegenerative diseases. Folic acid (FA) has been shown to act through DNA methyltransferase to stimulate NSC proliferation. To elucidate the underlying mechanism, the effect of FA on the methylation profiles in neonatal rat NSCs was assessed by methylated DNA immunoprecipitation (MeDIP) and methylated DNA immunoprecipitation-DNA microarray (MeDIP-Chip). Differentially methylated regions (DMRs) were determined by quantitative differentially methylated regions analysis, and genes carrying at least three DMRs were selected for pathway analysis. Gene network analysis revealed links with steroid biosynthesis, fatty acid elongation and the PI3K/Akt/CREB, neuroactive ligand-receptor interaction, Jak-STAT and MAPK signaling pathways. Moreover, Akt3 acted as a hub in the network, in which 14 differentially methylated genes converged to the PI3K/Akt/CREB signaling pathway. These findings indicate that FA stimulates NSC proliferation by modifying DNA methylation levels in the PI3K/Akt/CREB pathway.
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Suhui
authors.initials: S
authors.lastname: Luo
authors.affiliation: School of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Cardiology, General Hospital of Tianjin Medical University, Tianjin 300052, China.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY 14214-8028, USA.
authors.forename: John X
authors.initials: JX
authors.lastname: Wilson
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China. Electronic address: huangguowei@tmu.edu.cn.
authors.forename: Guowei
authors.initials: G
authors.lastname: Huang
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005492:Folic Acid / Q000494:pharmacology*; D053263:Gene Regulatory Networks / Q000187:drug effects; D008745:Methylation; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D005492:Folic Acid; D015254:DNA Modification Methylases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: DNA methylation; Folic acid; Neural stem cells; PI3K/Akt pathway; Proliferation