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Polycomb repressive complexes 1 and 2 independently and dynamically regulate euchromatin during cerebellar

Aditya Parmar1, Anjali Srinivasan1, Lena Krockenberger1

  • 1Department of Pathology, University of California San Diego, La Jolla, California, United States of America.

Plos Genetics
|September 29, 2025
PubMed
Summary

Polycomb Repressive Complexes (PRCs) fine-tune gene regulation in the developing mouse cerebellum. H2AK119ub deposition by PRC1 and H3K27me1 by PRC2 impact cis-regulatory elements and transcription, with uncoupled activities in mature brains.

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Area of Science:

  • Epigenetics and Neurodevelopment
  • Chromatin Biology
  • Gene Regulation

Background:

  • Polycomb Repressive Complexes (PRCs) regulate gene expression through histone modifications.
  • PRC1 deposits H2AK119ub, PRC2 deposits H3K27me3/me2/me1.
  • Epigenetic dysregulation is linked to neurodevelopmental disorders, but PRC roles in neurons are unclear.

Purpose of the Study:

  • To map PRC-dependent histone modifications in the developing mouse cerebellum.
  • To understand the dynamic roles of H2AK119ub and H3K27me1 in cerebellar neurodevelopment.
  • To investigate the functional consequences of these modifications on gene transcription.

Main Methods:

  • Chromatin Universal Endogenous Immunoprecipitation followed by sequencing (CUT&RUN) was employed.
  • Analysis was performed at two postnatal timepoints: day 12 and 3 months.
  • Histone modification patterns were compared between cerebellum, liver, and kidney.

Main Results:

  • H2AK119ub enriched in active enhancers and promoters during cerebellar maturation, distinct from heterochromatin.
  • H2AK119ub deposition occurred independently of H3K27me3, creating dynamic chromatin states.
  • H2AK119ub at promoters reduced downstream gene transcription; H3K27me1 localized to gene bodies.

Conclusions:

  • PRC1 (H2AK119ub) and PRC2 (H3K27me1) activities are uncoupled in the mature cerebellum.
  • These modifications likely fine-tune cis-regulatory element activity and transcription during development.
  • Cerebellar PRC deposition patterns are distinct from those in liver and kidney.