A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding platform.

Area of Science:

• Molecular Biology
• Epigenetics
• Cancer Research

Background:

• Mammalian SWI/SNF (BAF) chromatin remodeling complexes regulate DNA accessibility and gene expression.
• Mechanisms of targeting these master regulatory complexes to chromatin are not fully understood.

Purpose of the Study:

• To define the SWIFT domain as a transcription factor (TF) binding platform within the SMARCD subunits of SWI/SNF complexes.
• To investigate the role of SWIFT in TF interactions and its implications in cancer.

Main Methods:

• In vitro and cellular assays to demonstrate SWIFT's interaction with the PU.1 TF.
• Site-specific mutagenesis of SWIFT to assess the impact on TF interaction and complex targeting.
• Analysis of gene expression, cell proliferation, and TF sequestration in cancer cells.

Main Results:

• SWIFT acts as a direct binding platform for the transactivation domain of the TF PU.1.
• A single amino acid mutation in SWIFT abrogates PU.1 interaction, impairs complex targeting, and reduces proliferation in AML cells.
• Dominant SWIFT expression sequesters TFs, selectively killing TF-addicted cancer cells.

Conclusions:

• SWIFT is a conserved domain functioning as a universal TF binding platform for SWI/SNF complexes.
• Targeting SWIFT-TF interactions offers a potential strategy for modulating cell-type-specific transcription and treating cancers.
• This discovery provides insights into the precise targeting mechanisms of chromatin remodelers.