ZIC3 Controls the Transition from Naive to Primed Pluripotency

Abstract

Summary Embryonic stem cells (ESCs) must transition through a series of intermediate cell states before becoming terminally differentiated. Here, we investigated the early events in this transition by determining the changes in the open chromatin landscape as naive 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 following Zic3 depletion 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 upstream of a set of pro-differentiation transcriptional regulators and provide an important advance in our understanding of the regulatory factors governing the early steps in ESC differentiation.

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).…”

Adipocyte REVERBα dictates adipose tissue expansion during obesity

“…To define the cistrome, we used raw published gWAT ChIP-seq data (Zhang et al, 2015) to call 2,354 high-stringency REVERBα peaks. To infer which genes might be direct targets of REVERBα repression, we employed a custom Python script that calculates the enrichment of differentially expressed gene sets in spatial relation to identified transcription factor binding sites ( Figure 6 Supplemental A ) (Hunter et al, 2020; Yang et al, 2019), over all genes in the genome.…”

“…In order to calculate enrichment of RNA-seq-based gene clusters with respect to ChIP-seq peaks, we used our in-house custom tool (Yang et al, 2019) which calculates gene cluster enrichment within specified distances from the centre of peaks (see also Code Availability statement below). The tool extends peaks in both directions for the given distances and extracts all genes whose TSSs overlap with the extended peaks.…”

“…The custom Python code (Yang et al, 2019) used to carry out the peaks- genes enrichment analysis in this study is available at http://bartzabel.ls.manchester.ac.uk//Pete/PF5HZns0zv/pegs-0.2.0.tgz.…”

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

“…To identify Tcf3-independent functions of b-catenin, we analyzed DE genes of b-catenin-knockdown ESCs bound by b-catenin only ( Figures 3G 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-2g (Tfap2c) and BCL6B, which are implicated in PGC development (Ishii et al, 2012), adding more evidence to a role of b-catenin in regulating germ cell development (Figures S1I and S1J).…”