Cdk2ap1 is required for epigenetic silencing of Oct4 during murine embryonic stem cell differentiation.
Oct4 is a known master regulator of stem cell renewal and differentiation. Expression of Oct4 during differentiation is regulated by promoter methylation by the nucleosome remodeling and histone deacetylation (NuRD) complex. Here, we show that Cdk2ap1, a negative regulator of Cdk2 function and cell cycle, promotes Oct4 promoter methylation during murine embryonic stem cell differentiation to down-regulate Oct4 expression. We further show that this repressor function of Cdk2ap1 is dependent on its physical interaction with the methyl DNA-binding protein, Mbd3. Our data support a potential molecular link between the known differentiation promoters, including bone morphogenetic proteins and transforming growth factor signaling, and embryonic stem cell differentiation.
Deshpande
Amit M
AM
Dental Research Institute, UCLA School of Dentistry, Los Angeles, California 90025, USA. adeshpan@ucla.edu
Dai
Yan-Shan
YS
Kim
Yong
Y
Kim
Jeffrey
J
Kimlin
Lauren
L
Gao
Kai
K
Wong
David T
DT
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D020868:Gene Silencing / Q000502:physiology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D051379:Mice; D018345:Mice, Knockout; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C492013:Mbd3 protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C496849:Cdk2ap1 protein, mouse; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex