A role for NANOG in G1 to S transition in human embryonic stem cells through direct binding of CDK6 and CDC25A.
In this study, we show that NANOG, a master transcription factor, regulates S-phase entry in human embryonic stem cells (hESCs) via transcriptional regulation of cell cycle regulatory components. Chromatin immunoprecipitation combined with reporter-based transfection assays show that the C-terminal region of NANOG binds to the regulatory regions of CDK6 and CDC25A genes under normal physiological conditions. Decreased CDK6 and CDC25A expression in hESCs suggest that both CDK6 and CDC25A are involved in S-phase regulation. The effects of NANOG overexpression on S-phase regulation are mitigated by the down-regulation of CDK6 or CDC25A alone. Overexpression of CDK6 or CDC25A alone can rescue the impact of NANOG down-regulation on S-phase entry, suggesting that CDK6 and CDC25A are downstream cell cycle effectors of NANOG during the G1 to S transition.
Zhang
Xin
X
NorthEast England Stem Cell Institute, Institute of Human Genetics, Newcastle University, International Centre for Life, Newcastle upon Tyne, England, UK.
Neganova
Irina
I
Przyborski
Stefan
S
Yang
Chunbo
C
Cooke
Michael
M
Atkinson
Stuart P
SP
Anyfantis
George
G
Fenyk
Stefan
S
Keith
W Nicol
WN
Hoare
Stacey F
SF
Hughes
Owen
O
Strachan
Tom
T
Stojkovic
Miodrag
M
Hinds
Philip W
PW
Armstrong
Lyle
L
Lako
Majlinda
M
D049109:Cell Proliferation; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology*; D016193:G1 Phase; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000071317:Nanog Homeobox Protein; D039904:Pluripotent Stem Cells / Q000166:cytology*; D012045:Regulatory Sequences, Nucleic Acid; D016196:S Phase; D015398:Signal Transduction; D014158:Transcription, Genetic; D020687:cdc25 Phosphatases / Q000378:metabolism*
D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases