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

Stem Cell Reports. 2022 Jun 14;17(6):1334-1350. doi: 10.1016/j.stemcr.2022.04.016. Epub 2022 May 19.


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.

Keywords: 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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / genetics
  • Cell Differentiation / genetics
  • Embryonic Stem Cells* / metabolism
  • Endoderm*
  • Germ Layers