Nitric oxide repression of Nanog promotes mouse embryonic stem cell differentiation.
Exposure of mouse embryonic stem (mES) cells to high concentrations of chemical nitric oxide (NO) donors promotes differentiation, but the mechanisms involved in this process at the gene expression level are poorly defined. In this study we report that culture of mES cells in the presence of 0.25-1.0 mM diethylenetriamine nitric oxide adduct (DETA-NO) leads to downregulation of Nanog and Oct4, the two master genes involved in the control of the pluripotent state. This action of NO was also apparent in the human ES cell line, HS 181. The suppressive action of NO on Nanog gene depends on the activation of p53 repressor protein by covalent modifications, such as pSer15, pSer315, pSer392 and acetyl Lys 379. NO-induced repression of Nanog is also associated with binding of trimethylated histone H3 and pSer315 p53 to its promoter region. In addition, exposure to 0.5 mM DETA-NO induces early differentiation events of cells with acquisition of epithelial morphology and expression of markers of definitive endoderm, such as FoxA2, Gata4, Hfn1-beta and Sox 17. This phenotype was increased when cells were treated with valproic acid (VPA) for 10 days.
Mora-Castilla
S
S
Andalusian Center for Molecular Biology and Regenerative Medicine-University Pablo de Olavide, CIBERDEM, Seville, Spain.
Tejedo
J R
JR
Hmadcha
A
A
Cahuana
G M
GM
Martín
F
F
Soria
B
B
Bedoya
F J
FJ
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002460:Cell Line; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004707:Endoderm / Q000166:cytology; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D000071317:Nanog Homeobox Protein; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D006657:Histones; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D020030:Nitric Oxide Donors; D050814:Octamer Transcription Factor-3; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide