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The assembly of mammalian SWI/SNF chromatin remodeling complexes is regulated by lysine-methylation dependent

Pengfei Guo1, Nam Hoang1, Joseph Sanchez1

  • 1Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV, 89154, USA.

Nature Communications
|November 6, 2022
PubMed

Insights

Loss of LSD1 (Lysine-Specific Demethylase 1) causes SWI/SNF complex dissolution. LSD1 demethylates SMARCC1/SMARCC2, preventing their proteolysis and maintaining embryonic stem cell pluripotency.

Area of Science:

  • Chromatin remodeling
  • Epigenetics
  • Molecular biology

Background:

  • Mammalian SWI/SNF complexes are crucial for development, and their subunit loss can lead to cancer via proteolysis.
  • The precise mechanisms regulating SWI/SNF complex assembly and stability are not fully understood.

Purpose of the Study:

  • To investigate the role of LSD1/KDM1A in SWI/SNF complex integrity.
  • To identify the molecular players and mechanisms controlling SWI/SNF subunit stability and its impact on stem cell function.

Main Methods:

  • Mouse models with targeted gene deletions (Lsd1/Kdm1a, L3mbtl3).
  • Biochemical assays to assess protein levels and complex integrity.
  • Ubiquitin ligase complex analysis (CRL4DCAF5).
  • Assessment of embryonic stem cell pluripotency and self-renewal.

Main Results:

  • Lsd1 deletion led to SWI/SNF complex dissolution.
  • LSD1 demethylates lysine residues on SMARCC1 and SMARCC2, protecting them from proteolysis by L3MBTL3 and CRL4DCAF5.
  • SMARCC1 is identified as a key target for maintaining stem cell pluripotency.
  • L3mbtl3 deletion resulted in SWI/SNF component accumulation and embryonic lethality.

Conclusions:

  • SWI/SNF complex assembly is regulated by a lysine-methylation-dependent proteolytic pathway.
  • LSD1 and L3MBTL3 are critical regulators of SWI/SNF complex stability and embryonic stem cell function.

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