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Parallel PRC2/cPRC1 and vPRC1 pathways silence lineage-specific genes and maintain self-renewal in mouse embryonic

J A Zepeda-Martinez1, C Pribitzer1, J Wang2

  • 1Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria.

Science Advances
|April 10, 2020
PubMed

Insights

Polycomb Repressive Complexes (PRC1 and PRC2) maintain cell fate. Two independent PRC1 pathways (cPRC1 and vPRC1) ensure robust gene silencing, crucial for mouse embryonic stem cell self-renewal.

Area of Science:

  • Epigenetics and Gene Regulation
  • Developmental Biology
  • Stem Cell Biology

Background:

  • Polycomb Repressive Complexes (PRC1 and PRC2) are key transcriptional repressors essential for maintaining cell fate during embryonic development.
  • These complexes catalyze distinct histone modifications to establish repressive chromatin at shared target genes.
  • The precise cooperation mechanisms between canonical PRC1 (cPRC1), variant PRC1 (vPRC1), and PRC2 in gene silencing and mouse embryonic stem cell (mESC) self-renewal remain incompletely understood.

Purpose of the Study:

  • To elucidate the distinct roles and cooperation of cPRC1, vPRC1, and PRC2 in gene silencing and mESC self-renewal.
  • To investigate the functional redundancy and necessity of PRC1 pathways in maintaining epigenetic repression.
  • To understand how parallel silencing pathways contribute to robust gene regulation and prevent differentiation.

Main Methods:

  • Utilized combinatorial genetic perturbations in mESC models.
  • Assessed histone modifications, specifically H2A monoubiquitylation.
  • Analyzed gene expression profiles of lineage-specific genes and PRC1/PRC2 occupancy.

Main Results:

  • Identified independent pathways for cPRC1 and vPRC1 responsible for H2A monoubiquitylation and silencing of shared target genes.
  • Demonstrated that loss of either PRC2-dependent cPRC1 or PRC2-independent vPRC1 alone does not impair mESC self-renewal.
  • Showed that simultaneous loss of both pathways triggers mESC differentiation and activates lineage-specific genes targeted by high PRC1/PRC2 levels.

Conclusions:

  • Parallel functional pathways mediated by cPRC1 and vPRC1 explain the differential requirements for PRC1 and PRC2.
  • These parallel pathways provide robust and redundant silencing of lineage-specific genes, ensuring mESC self-renewal.
  • Disruption of these parallel pathways compromises epigenetic stability, leading to differentiation.

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