title: The Forkhead box transcription factor FOXM1 is required for the maintenance of cell proliferation and protection against oxidative stress in human embryonic stem cells.
abstract: Human embryonic stem cells (hESCs) exhibit unique cell cycle structure, self-renewal and pluripotency. The Forkhead box transcription factor M1 (FOXM1) is critically required for the maintenance of pluripotency in mouse embryonic stem cells and mouse embryonal carcinoma cells, but its role in hESCs remains unclear. Here, we show that FOXM1 expression was enriched in undifferentiated hESCs and was regulated in a cell cycle-dependent manner with peak levels detected at the G2/M phase. Expression of FOXM1 did not correlate with OCT4 and NANOG during in vitro differentiation of hESCs. Importantly, knockdown of FOXM1 expression led to aberrant cell cycle distribution with impairment in mitotic progression but showed no profound effect on the undifferentiated state. Interestingly, FOXM1 depletion sensitized hESCs to oxidative stress. Moreover, genome-wide analysis of FOXM1 targets by ChIP-seq identified genes important for M phase including CCNB1 and CDK1, which were subsequently confirmed by ChIP and RNA interference analyses. Further peak set comparison against a differentiating hESC line and a cancer cell line revealed a substantial difference in the genomic binding profile of FOXM1 in hESCs. Taken together, our findings provide the first evidence to support FOXM1 as an important regulator of cell cycle progression and defense against oxidative stress in hESCs.
authors.affiliation: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: C T D
authors.initials: CT
authors.lastname: Kwok
authors.affiliation: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: M H
authors.initials: MH
authors.lastname: Leung
authors.affiliation: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China; School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: J
authors.initials: J
authors.lastname: Qin
authors.affiliation: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Centre for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: cherielee@hku.hk.
authors.forename: Y L
authors.initials: YL
authors.lastname: Lee
authors.affiliation: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: kmyao@hku.hk.
authors.forename: K-M
authors.initials: KM
authors.lastname: Yao
mesh_terms: D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D000072278:Forkhead Box Protein M1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008856:Microscopy, Fluorescence; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D000072278:Forkhead Box Protein M1; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide
keywords: Cell proliferation; Chromatin immunoprecipitation-sequencing; FOXM1; Human embryonic stem cells; Oxidative stress; Pluripotency