Changes in PRC1 activity during interphase modulate lineage transition in pluripotent cells

Area of Science:

• Cell Biology
• Developmental Biology
• Epigenetics

Background:

• Pluripotent cells' differentiation potential varies across the cell cycle.
• Molecular mechanisms linking cell cycle phase to differentiation gene regulation are unclear.
• Polycomb group proteins are implicated in cell cycle-dependent gene expression.

Purpose of the Study:

• To investigate the role of Polycomb Repressive Complex 1 (PRC1) in cell-cycle-regulated differentiation of pluripotent cells.
• To elucidate how PRC1 activity changes during interphase and affects gene transcription.
• To understand the preference for G1 phase in initiating differentiation gene activation.

Main Methods:

• Assessed PRC1 recruitment and H2AK119 ubiquitination across cell cycle phases.
• Analyzed 3D chromatin interactions during interphase.
• Utilized genetic ablation of RING1B (PRC1 catalytic subunit) in mouse embryonic stem cells (mESCs).
• Studied transcriptional activation of differentiation genes upon retinoic acid stimulation.

Main Results:

• PRC1 recruitment and H2AK119 ubiquitination are higher in S and G2 phases than G1.
• Cells in S and G2 phases exhibit stronger repression of developmental genes, dependent on PRC1's RING1B.
• Depletion of RING1B disrupts the G1-phase preference for differentiation gene activation in mESCs.
• Increased polycomb activity during interphase progression limits response to developmental cues in S/G2 phases.

Conclusions:

• PRC1 activity incrementally increases during interphase, leading to enhanced repression of differentiation genes in S and G2 phases.
• This cell-cycle-dependent repression facilitates the preferential activation of differentiation genes in the G1 phase.
• The findings reveal a mechanism for cell-cycle-regulated differentiation in pluripotent stem cells.