Journal
EMBO JOURNAL
Volume 32, Issue 16, Pages 2231-2247Publisher
WILEY
DOI: 10.1038/emboj.2013.161
Keywords
DNA-independent interaction; hydrophobic stacking; pluripotency; protein interactome; SELEX
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Funding
- Wellcome Trust
- IC
- EU Framework 7 project 'EuroSyStem'
- VIDI grant (NWO)
- Netherlands Institute of Regenerative Medicine network
- ASTIL Regione Lombardia [16874, GGP12152, 2010-0673, IG-5801]
- Medical Research Council [G0901533, G0700711B] Funding Source: researchfish
- Associazione Italiana per la Ricerca sul Cancro Funding Source: Custom
- Fondazione Telethon Funding Source: Custom
- MRC [G0901533] Funding Source: UKRI
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Embryonic stem (ES) cell self-renewal efficiency is determined by the Nanog protein level. However, the protein partners of Nanog that function to direct self-renewal are unclear. Here, we identify a Nanog interactome of over 130 proteins including transcription factors, chromatin modifying complexes, phosphorylation and ubiquitination enzymes, basal transcriptional machinery members, and RNA processing factors. Sox2 was identified as a robust interacting partner of Nanog. The purified Nanog-Sox2 complex identified a DNA recognition sequence present in multiple overlapping Nanog/Sox2 ChIP-Seq data sets. The Nanog tryptophan repeat region is necessary and sufficient for interaction with Sox2, with tryptophan residues required. In Sox2, tyrosine to alanine mutations within a triple-repeat motif (S X T/S Y) abrogates the Nanog-Sox2 interaction, alters expression of genes associated with the Nanog-Sox2 cognate sequence, and reduces the ability of Sox2 to rescue ES cell differentiation induced by endogenous Sox2 deletion. Substitution of the tyrosines with phenylalanine rescues both the Sox2-Nanog interaction and efficient self-renewal. These results suggest that aromatic stacking of Nanog tryptophans and Sox2 tyrosines mediates an interaction central to ES cell self-renewal.
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