The SWI/SNF PBAF complex facilitates REST occupancy at repressive chromatin

Area of Science:

• Molecular Biology
• Cancer Genomics
• Epigenetics

Background:

• Switch/sucrose non-fermentable (SWI/SNF) chromatin remodelers are essential for cellular function.
• Mutations in SWI/SNF subunits, like ARID2 in the polybromo-associated BAF (PBAF) complex, are implicated in various cancers, including melanoma.

Purpose of the Study:

• To investigate the specific role of the PBAF complex in melanocytes and melanoma.
• To elucidate the function of ARID2 within the PBAF complex in regulating chromatin accessibility and gene expression.

Main Methods:

• Epigenomic profiling of SWI/SNF complexes and chromatin states.
• Time-resolved analyses of ATPase inhibition sensitivity.
• Investigation of REST transcription factor binding in wild-type and ARID2-deficient cells.

Main Results:

• PBAF regions exhibit distinct sensitivity to ATPase inhibition compared to BAF sites.
• PBAF selectively targets Polycomb-repressed chromatin enriched for the RE1 silencing transcription factor (REST).
• ARID2 loss impairs REST binding, leading to the upregulation of synaptic transcripts, a signature found in ARID2-mutant melanoma and brain metastases.

Conclusions:

• The PBAF complex uniquely facilitates transcription factor access to repressed chromatin.
• ARID2's role in PBAF is critical for repressing neuronal gene expression in melanoma.
• This mechanism has significant implications for understanding melanoma progression and metastasis.