Distinct SoxB1 networks are required for naïve and primed pluripotency

Abstract

Deletion of Sox2 from mouse embryonic stem cells (ESCs) causes trophectodermal differentiation. While this can be prevented by enforced expression of the related SOXB1 proteins, SOX1 or SOX3, the roles of SOXB1 proteins in epiblast stem cell (EpiSC) pluripotency are unknown. Here, we show that Sox2 can be deleted from EpiSCs with impunity. This is due to a shift in the balance of SoxB1 expression in EpiSCs, which have decreased Sox2 and increased Sox3 compared to ESCs. Consistent with functional redundancy, Sox3 can also be deleted from EpiSCs without eliminating self-renewal. However, deletion of both Sox2 and Sox3 prevents self-renewal. The overall SOXB1 levels in ESCs affect differentiation choices: neural differentiation of Sox2 heterozygous ESCs is compromised, while increased SOXB1 levels divert the ESC to EpiSC transition towards neural differentiation. Therefore, optimal SOXB1 levels are critical for each pluripotent state and for cell fate decisions during exit from naïve pluripotency.

Functional Dissection of the Enhancer Repertoire in Human Embryonic Stem Cells

“…We find a consistent contribution of evolutionary conservation and GC/CG dinucleotide frequencies to enhancer activity. Notably, the relative importance of TF binding motifs shifts slightly between naive and primed: e.g., ZIC3 is linked to naive ESCs ( Warrier et al., 2017 ), and SOX3 is linked to primed ESCs, in line with a recent report on primed pluripotent mouse cells ( Corsinotti et al., 2017 ).…”

Sox2 modulation increases naïve pluripotency plasticity

“…Gene ontology enrichment for genes differentially expressed between Sox2-low iPSCs and control iPSCs revealed only 325 differentially expressed genes between the different genotypes with no strongly enriched GO terms ( Figures S4 B and Data S1 ). In addition, no Sox family member gene was found upregulated in Sox2-low iPSCs, eliminating that way possible functional redundancy ( Corsinotti et al., 2017 ). In agreement with Sox2-low iPSCs having a naive identity they clustered closely with control iPSCs, ESCs and E4.5 naive epiblast cells and separate from embryo trophoblast/trophectoderm (TE) cells ( Figure 6 A).…”

Dynamic regulation of chromatin accessibility by pluripotency transcription factors across the cell cycle

“…While we found a larger influence on chromatin accessibility upon depletion of OCT4 than SOX2, we cannot fully exclude that this is partly caused by differences in protein half-lives or cell lines. Regions bound but not regulated by SOX2, including OD loci, could in principle also be controlled by other SOX family members such as SOX3 or SOX15 (Corsinotti et al, 2017; Masui et al, 2007). As OCT4 depletion affects accessibility already after 30 min, we can also not exclude that some of the changes in accessibility observed after long-term (24–40 hr) depletion may be due to secondary effects.…”