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

Area of Science:

• Developmental biology
• Stem cell biology
• Cell cycle regulation

Background:

• Cell cycle progression and differentiation decisions in embryonic stem cells (ESCs) are interconnected but poorly understood.
• The specific mechanisms governing these linked processes remain elusive.

Purpose of the Study:

• To investigate the relationship between cell cycle states and differentiation potential in ESCs.
• To identify molecular drivers that dictate lineage specification based on cell cycle phase.

Main Methods:

• Utilized a cell-cycle reporter system combined with single-cell RNA sequencing (scRNA-seq) to profile ESC transcriptomes across cell cycle phases.
• Applied retinoic acid to G1 and G2/M phase ESCs to assess differentiation capacity.
• Analyzed enhancer chromatin states in wild-type and Esrrb knockout ESCs.

Main Results:

• Both G1 and G2/M ESCs could differentiate into epiblast stem cells (EpiSCs).
• Only G2/M ESCs differentiated into extraembryonic endoderm stem cells (XENs).
• The pluripotency factor Esrrb, upregulated in G2/M, drives XEN differentiation and associates with poised XEN enhancers.

Conclusions:

• Esrrb expression and cell cycle state are critical determinants for XEN differentiation potential.
• ESRRB is essential for ESCs to exit pluripotency towards the XEN lineage.
• This study uncovers a crucial link between Esrrb, cell cycle progression, and lineage specification during pluripotency exit.