The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells

Abstract

Oct4 and Nanog are transcription factors required to maintain the pluripotency and self-renewal of embryonic stem (ES) cells. Using the chromatin immunoprecipitation paired-end ditags method, we mapped the binding sites of these factors in the mouse ES cell genome. We identified 1,083 and 3,006 high-confidence binding sites for Oct4 and Nanog, respectively. Comparative location analyses indicated that Oct4 and Nanog overlap substantially in their targets, and they are bound to genes in different configurations. Using de novo motif discovery algorithms, we defined the cis-acting elements mediating their respective binding to genomic sites. By integrating RNA interference-mediated depletion of Oct4 and Nanog with microarray expression profiling, we demonstrated that these factors can activate or suppress transcription. We further showed that common core downstream targets are important to keep ES cells from differentiating. The emerging picture is one in which Oct4 and Nanog control a cascade of pathways that are intricately connected to govern pluripotency, self-renewal, genome surveillance and cell fate determination.

Ube2s regulates Sox2 stability and mouse ES cell maintenance

“…2,3,25,[48][49][50] However, knowledge regarding the precise mechanisms underlying how Sox2 is posttranslationally regulated remains limited. Several studies have shown that the protein activity of Sox2 can be modified by sumoylation, methylation, acetylation and phosphorylation.…”

Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

“…Nanog was identified as the key component to maintain the pluripotency of the embryonic stem, together with Oct4 and Sox2 (Boyer et al, 2005;Loh et al, 2006). Nanog/Oct4 expression confers selfrenewal in a leukemia inhibitory factor (LIF)/STAT3-independent manner and blocks specifically all differentiation processes (Mitsui et al, 2003).…”

“…Moreover, t(4;11) patient cells showed active transcription of Oct4 and Bmi1, two genes selectively expressed in stem cells. However, no transcriptional activity was found for Sox2, the third component identified in the core Nanog network (Boyer et al, 2005;Loh et al, 2006). Sox2 is a minor-groove DNA binding protein that is involved in the transcriptional activation of the Nanog gene, but is presumably dispensable if Nanog (or a retrogene thereof) is already transcriptionally active.…”

Two-Phase Analysis of Molecular Pathways Underlying Induced Pluripotent Stem Cell Induction

“…Based on genome-wide mapping of transcription factor targets, recent studies have revealed that ESC pluripotency is mainly directed by the interconnected autoregulatory loop of Oct4, Sox2, and Nanog, and by subsequent transcriptional networks, which enhance transcription of pluripotency genes and repress genes associated with differentiation [14][15][16][17][18][19]. The networks important for ESC pluripotency and self-renewal may not contribute to the iPSC induction, however, as endogenous Nanog is not present at the early phase of reprogramming [17], and the promoters of Oct4 and Sox2 are not available for self-activation, due to DNA methylation [20].…”