Context-Dependent Functions of NANOG Phosphorylation in Pluripotency and Reprogramming.
The core pluripotency transcription factor NANOG is critical for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. Although NANOG is phosphorylated at multiple residues, the role of NANOG phosphorylation in ESC self-renewal is incompletely understood, and no information exists regarding its functions during reprogramming. Here we report our findings that NANOG phosphorylation is beneficial, although nonessential, for ESC self-renewal, and that loss of phosphorylation enhances NANOG activity in reprogramming. Mutation of serine 65 in NANOG to alanine (S65A) alone has the most significant impact on increasing NANOG reprogramming capacity. Mechanistically, we find that pluripotency regulators (ESRRB, OCT4, SALL4, DAX1, and TET1) are transcriptionally primed and preferentially associated with NANOG S65A at the protein level due to presumed structural alterations in the N-terminal domain of NANOG. These results demonstrate that a single phosphorylation site serves as a critical interface for controlling context-dependent NANOG functions in pluripotency and reprogramming.
['Saunders|Arven|A|', 'Li|Dan|D|', 'Faiola|Francesco|F|', 'Huang|Xin|X|', 'Fidalgo|Miguel|M|', 'Guallar|Diana|D|', 'Ding|Junjun|J|', 'Yang|Fan|F|', 'Xu|Yang|Y|', 'Zhou|Hongwei|H|', 'Wang|Jianlong|J|']
D000818:Animals D002460:Cell Line D002478:Cells, Cultured D065150:Cellular Reprogramming D057137:DAX-1 Orphan Nuclear Receptor D004268:DNA-Binding Proteins D053595:Embryonic Stem Cells D057026:Induced Pluripotent Stem Cells D051379:Mice D020125:Mutation, Missense D000071317:Nanog Homeobox Protein D050814:Octamer Transcription Factor-3 D010766:Phosphorylation D000072417:Protein Domains D011499:Protein Processing, Post-Translational D011518:Proto-Oncogene Proteins D011960:Receptors, Estrogen D014157:Transcription Factors
pluripotency reprogramming self-renewal iPSC phospho-NANOG post-translational modification serine to alanine mutation