Esrrb is a cell-cycle-dependent associated factor balancing pluripotency and XEN differentiation

Sapir Herchcovici Levy, Sharon Feldman Cohen, Lee Arnon, Shlomtzion Lahav, Muhammad Awawdy, Adi Alajem, Danny Bavli, Xue Sun, Yosef Buganim, Oren Ram*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Cell cycle and differentiation decisions are linked; however, the underlying principles that drive these decisions are unclear. Here, we combined cell-cycle reporter system and single-cell RNA sequencing (scRNA-seq) profiling to study the transcriptomes of embryonic stem cells (ESCs) in the context of cell-cycle states and differentiation. By applying retinoic acid, to G1 and G2/M ESCs, we show that, while both populations can differentiate toward epiblast stem cells (EpiSCs), only G2/M ESCs could differentiate into extraembryonic endoderm cells. We identified Esrrb, a pluripotency factor that is upregulated during G2/M, as a driver of extraembryonic endoderm stem cell (XEN) differentiation. Furthermore, enhancer chromatin states based on wild-type (WT) and ESRRB knockout (KO) ESCs show association of ESRRB with XEN poised enhancers. G1 cells overexpressing Esrrb allow ESCs to produce XENs, while ESRRB-KO ESCs lost their potential to differentiate into XEN. Overall, this study reveals a vital link between Esrrb and cell-cycle states during the exit from pluripotency.

Original languageAmerican English
Pages (from-to)1334-1350
Number of pages17
JournalStem Cell Reports
Issue number6
StatePublished - 14 Jun 2022

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  • ChIP-seq and single-cell RNA-seq (scRNA-seq)
  • Esrrb transcription factor
  • Exit from pluripotency
  • cell cycle
  • cellular differentiation and lineage specification
  • embryonic stem cells
  • epiblast stem cells (EpiSC)
  • extraembryonic endoderm stem cells(XEN)


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