4.6 Article

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

Journal

STEM CELL REPORTS
Volume 17, Issue 6, Pages 1334-1350

Publisher

CELL PRESS
DOI: 10.1016/j.stemcr.2022.04.016

Keywords

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Funding

  1. European Research Council (ERC) [715260]
  2. Israeli Center of Research Excellence (I-CORE) program
  3. Israel Science Foundation (ISF) [1618/16]
  4. Azriely Foundation Scholar Program for Distinguished Junior Faculty
  5. European Union [765966]
  6. European Research Council (ERC) [715260] Funding Source: European Research Council (ERC)
  7. Marie Curie Actions (MSCA) [765966] Funding Source: Marie Curie Actions (MSCA)

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This study reveals the relationship between Esrrb and differentiation of embryonic stem cells, and identifies Esrrb as a driver of extraembryonic endoderm cell differentiation during the G2/M phase.
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.

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