A direct physical interaction between Nanog and Sox2 regulates embryonic stem cell self-renewal

Abstract

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.

Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia

“…The lineagerestricted effect of NANOG is compatible with the existence of tissue-specific partners. Although the nature of these hypothetical partners is presently unknown, SOX2 is a good candidate due to its expression pattern 18 and its ability to interact with NANOG in ESCs 11 .…”

“…NANOG exerts its role in pluripotency in tight cooperation with two other pluripotency transcription factors, OCT4 (also known as POU5F1) and SOX2. Together, these three factors form a core transcriptional regulatory network essential for the acquisition and maintenance of ESC identity [7][8][9][10][11][12] . During mouse embryogenesis, these factors are highly expressed in the inner cell mass and their deletion causes early embryonic lethality 3,13,14 .…”

DPPA2 Protein Expression is Associated with Gastric Cancer Metastasis

“…These findings may indicate a shared function for DPPA2 in embryonic stem cells and cancer stem cells showing that some functions in embryogenesis, specifically restricted to the stage of the emergence and/ or maintenance of the embryonic stem cell, are generally involved in the cancer stem cell phenotype (Monk et al, 2008). Probably there is a close relationship between DPPA2 and pluripotency genes regulatory network consisting of OCT4, SOX2, NANOG, SALL4, and DPPA4 (Yang et al, 2008;Gagliardi et al, 2013;Forghanifard et al, 2014). Furthermore, it has been illustrated that Dppa4, as well as components of the pluripotency regulatory network, is required for self-renewal, interestingly (Ivanova et al, 2006).…”

“…SAP domain of the DPPA2 protein plays important role in chromatin organization and RNA processing. DPPA2 is correlated to a closely linked gene, DPPA4, on human chromosome 3 (Gagliardi et al, 2013). It has been reported that there are similarities between DPPA2 and DPPA4 (Tung et al, 2013).…”

A New Role of Hindbrain Boundaries as Pools of Neural Stem/Progenitor Cells Regulated by Sox2

“…It plays key roles during CNS development, such as in survival, proliferation and maintenance of NSCs [48][49][50], as well as in the acquisition of neural/glial identity [51][52][53][54][55][56][57][58][59][60][61]. As expected from the key role of Sox2 in neural progenitor cells (NPCs), previous studies have shown that early in neural tube development, Sox2 is expressed along the entire hindbrain [62,63].…”