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CARM1-mediated methylation of ASXL2 impairs tumor-suppressive function of MLL3/COMPASS

Zibo Zhao1, Emily Jane Rendleman1, Aileen Patricia Szczepanski1

  • 1Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, 303 East Superior Street, Chicago, IL 60611, USA.

Science Advances
|October 5, 2022
PubMed

Insights

ASXL2 directly binds to MLL3/COMPASS, mediating BAP1

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Biology

Background:

  • Polycomb and Trithorax complexes regulate gene expression and are implicated in cancer.
  • BRCA1 associated protein-1 (BAP1) deubiquitinase regulates Polycomb activity and recruits MLL3/COMPASS to tumor suppressor gene enhancers.
  • The BAP1-MLL3 pathway is frequently mutated in various cancers.

Purpose of the Study:

  • To elucidate the mechanism by which BAP1 recruits MLL3/COMPASS to target gene loci.
  • To investigate the role of ASXL2 in mediating the BAP1-MLL3 interaction.
  • To identify regulatory mechanisms controlling the BAP1-MLL3-COMPASS axis.

Main Methods:

  • Co-immunoprecipitation assays to demonstrate ASXL2-MLL3 interaction.
  • Chromatin immunoprecipitation sequencing (ChIP-seq) to assess MLL3 occupancy.
  • Quantitative PCR (qPCR) to measure gene expression levels.
  • Mass spectrometry to identify ASXL2 methylation sites.

Main Results:

  • ASXL2 subunit of the BAP1 complex directly interacts with MLL3/COMPASS.
  • Loss of ASXL2 leads to reduced MLL3 binding at enhancers and decreased target gene expression.
  • Protein arginine methyltransferase 4 (PRMT4/CARM1) methylates ASXL2 at R639/R641, inhibiting MLL3 binding.
  • CARM1-mediated methylation of ASXL2 represses MLL3/COMPASS-dependent gene expression.

Conclusions:

  • ASXL2 is a crucial mediator of BAP1 recruitment of MLL3/COMPASS to target enhancers.
  • PRMT4/CARM1 antagonizes the BAP1-MLL3-COMPASS transcriptional activation complex through ASXL2 methylation.
  • This study reveals a novel repressive role for CARM1 and identifies a potential therapeutic target in the BAP1-MLL3-COMPASS pathway for cancer treatment.

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