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Polycomb repression of Hox genes involves spatial feedback but not domain compaction or phase-transition

ABSTRACT: Polycomb group proteins play a critical role in silencing transcription during development. It is commonly proposed that Polycomb dependent changes in genome folding, which compact chromatin, contribute directly to repression by blocking binding of activating complexes. Recently, it has also been argued that liquid-liquid demixing of Polycomb proteins facilitates this compaction and repression by phase-separating target genes into a membraneless compartment. To test these models, we utilized Optical Reconstruction of Chromatin Architecture (ORCA) to trace the Hoxa gene cluster, a canonical Polycomb target, in thousands of single cells. Across multiple cell types, we find that Polycomb-bound chromatin frequently explores decompact states and partial mixing with neighboring chromatin, while remaining uniformly repressed, challenging the repression-by-compaction or phase-separation models. Using polymer simulations, we show that these observed flexible ensembles can be explained by “spatial feedback”: transient contacts that contribute to propagation of the epigenetic state, (epigenetic memory) without inducing a globular organization.

ORGANISM(S): Mus musculus

PROVIDER: GSE237501 | GEO | 2024/02/08

REPOSITORIES: GEO

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HP1β dependent phase separation regulates embryonic stem cells exit from naïve pluripotent state

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Dispersal of PRC1 condensates disrupts polycomb chromatin domains and loops

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A Polycomb domain found in committed cells impairs differentiation when introduced into PRC1 in pluripotent cells (ChIP-seq, CUT&RUN datasets)

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