Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells

Abstract

The transcription factors OCT4, SOX2, and NANOG have essential roles in early development and are required for the propagation of undifferentiated embryonic stem (ES) cells in culture. To gain insights into transcriptional regulation of human ES cells, we have identified OCT4, SOX2, and NANOG target genes using genome-scale location analysis. We found, surprisingly, that OCT4, SOX2, and NANOG co-occupy a substantial portion of their target genes. These target genes frequently encode transcription factors, many of which are developmentally important homeodomain proteins. Our data also indicate that OCT4, SOX2, and NANOG collaborate to form regulatory circuitry consisting of autoregulatory and feedforward loops. These results provide new insights into the transcriptional regulation of stem cells and reveal how OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal.

Changing POU dimerization preferences converts Oct6 into a pluripotency inducer

“… Position weight matrices obtained using de novo motif discovery (HOMER) and ChIP‐Seq summits of Oct4 in mouse ESCs 56, Brn2 in MEFs 48 h after transfections, and Brn2 in mouse NPCs 23.Molecular models based on the crystal structures previously published 44 represent configurations of two dimers on DNA: Sox2–Oct4 heterodimer (B) and Oct6–Oct6 homodimer (C). Oct4 POU domain, green; Oct4/Oct6 linker region, magenta; Sox2 HMG, cyan; Oct6 POU domain, orange.…”

“…Position weight matrices obtained using de novo motif discovery (HOMER) and ChIP‐Seq summits of Oct4 in mouse ESCs 56, Brn2 in MEFs 48 h after transfections, and Brn2 in mouse NPCs 23.…”

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).…”

Rôle des facteurs de transcription FoxO dans la maintenance des cellules souches

“…Inversement, une augmentation du niveau de PML entraîne la répression de l'expression de TBX2. Dans le contexte de la sénescence, il est probable que d'autres facteurs que l'oncogène Ras et p53 [5,6,8], qui restent à découvrir, activent l'expression de PML. Dans le cas du cancer, il a été montré que la fonction de PML est fréquemment supprimée.…”

“…En revanche, des expériences d'immunopré-cipitation de la chromatine, de gels retard et de tests luciférase ont montré que FoxO1 contrôle directement l'expression des gènes pluripotents OCT4 et SOX2, en occupant et activant leurs promoteurs respectifs (Figure 1). Notre étude met également en évidence quelques diffé-rences phénotypiques entre CSEh et CSEm pouvant refléter la différence temporelle gènes gouvernant la pluripotence et répri-ment des gènes requis pour la différencia-tion cellulaire [5]. Dans ce contexte, nous avons identifié récemment un nouveau composant du réseau transcriptionnel des CSE : FoxO1 [6] (Figure 1).…”