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Global identification of SWI/SNF targets reveals compensation by EP400

Benjamin J E Martin1, Eileen F Ablondi2, Christine Goglia2

  • 1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA.

Cell
|November 3, 2023
PubMed

Insights

A new SWI/SNF inhibitor reveals chromatin remodeling targets and identifies EP400/TIP60 as a compensatory mechanism. This finding predicts cancer cell sensitivity to SWI/SNF inhibition, improving therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Genomics
  • Cancer Research

Background:

  • Mammalian SWI/SNF complexes regulate DNA accessibility by moving nucleosomes.
  • Mutations in SWI/SNF are common in diseases, but therapeutic targets remain unclear.

Purpose of the Study:

  • To identify direct SWI/SNF targets and functional consequences using a novel inhibitor.
  • To explore compensatory mechanisms and predict therapeutic sensitivity.

Main Methods:

  • Utilized a fast-acting SWI/SNF inhibitor to block chromatin remodeling.
  • Assessed global chromatin accessibility and transcription changes.
  • Analyzed compensatory roles of EP400/TIP60 and synthetic lethality in cancer cells.

Main Results:

  • SWI/SNF inhibition led to rapid, global loss of chromatin accessibility and transcription.
  • EP400/TIP60 compensated for SWI/SNF loss at promoters, but not enhancers.
  • Synthetic lethality between EP400 and SWI/SNF was observed in cancer cell lines and patient data.

Conclusions:

  • Identified molecular genomic features predicting SWI/SNF inhibitor sensitivity in cancer.
  • Demonstrated a compensatory role for EP400/TIP60, revealing synthetic lethality.
  • Enhanced the therapeutic potential of SWI/SNF inhibitors by predicting drug sensitivity.
Keywords:
BRG1EP400PRO-seqRNAPIISWI/SNFchromatin accessibilitychromatin remodelingcombination therapiesepigenetic regulatorstranscription

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