ZIC3 controls the transition from naïve to primed pluripotency.

Abstract

Embryonic stem cells (ESCs) are pluripotent in nature, meaning that they have the capacity to differentiate into any cell in the body. However, to do so they must transition through a series of intermediate cell states before becoming terminally differentiated. A lot is known about how ESCs maintain their pluripotent state but comparatively less about how they exit this state and begin the transition towards differentiated cells. Here we investigated the earliest events in this transition by determining the changes in the open chromatin landscape as naïve mouse ESCs transition to epiblast-like cells (EpiLCs). Motif enrichment analysis of the newly opening regions coupled with expression analysis identified ZIC3 as a potential regulator of this cell fate transition. Chromatin binding and genome-wide transcriptional profiling confirmed ZIC3 as an important regulatory transcription factor and among its targets are genes encoding a number of transcription factors. Among these is GRHL2 which acts through enhancer switching to maintain the expression of a subset of genes from the ESC state. Our data therefore place ZIC3 at the top of a cascade of transcriptional regulators and provide an important advance in our understanding of the regulatory factors governing the earliest steps in ESC differentiation. 3

STARR-seq identifies active, chromatin-masked, and dormant enhancers in pluripotent mouse embryonic stem cells

“…This increased propensity of Zic3 −/− ESCs to differentiate towards the endodermal linage has been shown before for cells cultured in SL [56] and could be associated with the diminished expression of key pluripotency genes like Nanog and Prdm14, repressors of the (extraembryonic) endodermal lineage [56,79]. Zic3 has also been shown to interact with primed pluripotency genes like Otx2 and Oct4 [31] and was recently identified as a key driver of the transition from naïve to primed pluripotency [80]. Loss of Zic3 may therefore block the transition towards epiblast-like cells, resulting in cells that adopt an early endodermal cell fate when their pluripotency network is compromised.…”

Integrative and perturbation-based analysis of the transcriptional dynamics of TGFβ/BMP system components in transition from embryonic stem cells to neural progenitors

“…For example, at least two of the previously discussed Id genes, Id1 and Id2 , comprise an interesting co‐expression module together with Zic3 . These genes seem to be both upregulated in BMP4‐exposed cells (B4) and more differentiated cells (N4) without addition of any cytokines (Figure S6C,D), which is in line with their proposed roles in both maintenance and exit of pluripotency . To further illustrate the relevance of these co‐expression modules, we highlighted a set of four typical genes for four particular modules (Figure B) that show distinct expression profiles over all time points (Figure C).…”

“…For example, at least two of the These genes seem to be both upregulated in BMP4-exposed cells (B4) and more differentiated cells (N4) without addition of any cytokines ( Figure S6C, D), which is in line with their proposed roles in both maintenance and exit of pluripotency. 66,67 To further illustrate the relevance of these co-expression modules, we highlighted a set of four typical genes for four particular modules ( Figure 5B) that show distinct expression profiles over all time points ( Figure 5C). The first module displays high expression of core pluripotency genes (Tbx3, Klf4, Nanog, and Esrrb) that immediately drop in expression between B4 and N2, when cells enter the EpiLC stage.…”

β-Catenin and Associated Proteins Regulate Lineage Differentiation in Ground State Mouse Embryonic Stem Cells

“…To identify Tcf3-independent functions of β-catenin, we analyzed DE genes of β-catenin-knockdown ESCs bound by β-catenin only ( Figures 3 G and 3H). We found TF DNA motifs including Sp1, Klf4/5 (early embryonic development and pluripotency ( Marin et al., 1997 )), and Zic3 (transition from naive to primed pluripotency ( Yang et al., 2019 )). Furthermore, we found enriched motifs of Ap-2γ (Tfap2c) and BCL6B, which are implicated in PGC development ( Ishii et al., 2012 ), adding more evidence to a role of β-catenin in regulating germ cell development ( Figures S1 I and S1J).…”