mSWI/SNF promotes Polycomb repression both directly and through genome-wide redistribution

Area of Science:

• Epigenetics and Gene Regulation
• Chromatin Remodeling
• Stem Cell Biology

Background:

• The SWI/SNF (BAF) complex antagonizes Polycomb-mediated repression.
• BAF also paradoxically promotes Polycomb repression in stem cells and cancer.
• The dual role of BAF in Polycomb repression is mechanistically unclear.

Purpose of the Study:

• To investigate the dynamic interplay between the BAF complex and Polycomb repressive complexes (PRCs).
• To elucidate how BAF influences Polycomb localization and function in mouse embryonic stem cells.
• To understand the mechanisms underlying BAF's opposing roles in Polycomb-mediated gene silencing.

Main Methods:

• Utilized targeted protein degradation to rapidly deplete the BAF complex in mouse embryonic stem cells.
• Analyzed the redistribution of Polycomb repressive complexes PRC1 and PRC2 upon BAF depletion.
• Assessed changes in chromatin accessibility, epigenomic features, and gene expression.

Main Results:

• Rapid BAF depletion caused PRC1 and PRC2 to move from highly occupied sites (e.g., Hox clusters) to weakly occupied sites.
• This redistribution led to decompaction of repressed domains, gain of active epigenomic marks, and transcriptional derepression.
• Dose-dependent degradation of PRC1 and PRC2 revealed a conventional role for BAF in Polycomb repression, distinct from global redistribution.

Conclusions:

• BAF complex depletion induces a rapid redistribution of Polycomb repressive complexes, impacting chromatin state and gene expression.
• BAF plays a dual role: antagonizing Polycomb at some sites while conventionally promoting repression at others.
• These findings offer new mechanistic insights into the dynamic Polycomb-Trithorax axis regulation in stem cells.