title: Heterogeneous nuclear ribonucleoprotein A2/B1 regulates the self-renewal and pluripotency of human embryonic stem cells via the control of the G1/S transition.
abstract: Self-renewal and pluripotency of human embryonic stem cells (hESCs) are a complex biological process for maintaining hESC stemness. However, the molecular mechanisms underlying these special properties of hESCs are not fully understood. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) is a multifunctional RNA-binding protein whose expression is related to cell proliferation and carcinogenesis. In this study, we found that hnRNP A2/B1 expression was localized to undifferentiated hESCs and decreased upon differentiation of hESCs. hnRNP A2/B1 knockdown reduced the number of alkaline phosphatase-positive colonies in hESCs and led to a decrease in the expression of pluripotency-associated transcription factors OCT4, NANOG, and SOX2, indicating that hnRNP A2/B1 is essential for hESC self-renewal and pluripotency. hnRNP A2/B1 knockdown increased the expression of gene markers associated with the early development of three germ layers, and promoted the process of epithelial-mesenchymal transition, suggesting that hnRNP A2/B1 is required for maintaining the undifferentiated and epithelial phenotypes of hESCs. hnRNP A2/B1 knockdown inhibited hESC proliferation and induced cell cycle arrest in the G0/G1 phase before differentiation via degradation of cyclin D1, cyclin E, and Cdc25A. hnRNP A2/B1 knockdown increased p27 expression and induced phosphorylation of p53 and Chk1, suggesting that hnRNP A2/B1 also regulates the G1/S transition of hESC cell cycle through the control of p27 expression and p53 and Chk1 activity. Analysis of signaling molecules further revealed that hnRNP A2/B1 regulated hESC proliferation in a PI3K/Akt-dependent manner. These findings provide for the first time mechanistic insights into how hnRNP A2/B1 regulates hESC self-renewal and pluripotency.
authors.affiliation: Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul, Korea.
authors.forename: Hong Seo
authors.initials: HS
authors.lastname: Choi
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Lee
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Jang
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
authors.forename: Chun Jeih
authors.initials: CJ
authors.lastname: Ryu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D018920:Coculture Techniques; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D016193:G1 Phase / Q000502:physiology; D055785:Gene Knockdown Techniques; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D014162:Transfection
chemical_list: D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C439768:hnRNP A2; D019869:Phosphatidylinositol 3-Kinases
keywords: G1/S transition; Human embryonic stem cells; PI3K/Akt; Pluripotency; Self-renewal; hnRNP A2/B1