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ARID1A regulates histone octamer transfer activity of human canonical BAF complex
Naoe Moro1, Yukiko Fujisawa-Tanaka1, Shinya Watanabe1
1Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, United States.
Abstract:
Mutations that impact subunits of mammalian SWI/SNF (mSWI/SNF or BAF) chromatin remodeling complexes are found in over 20% of human cancers. Among these subunits, AT-rich interactive domain-containing protein 1A (ARID1A) is the most frequently mutated gene, occurring in over 8% of various cancers. The majority of ARID1A mutations are frameshift or nonsense mutations, causing loss of function. Previous studies have suggested that ARID1A may facilitate interactions between BAF complexes and various transcriptional coactivators, but a biochemical role for ARID1A in BAF remodeling activity has not been identified. Here, we describe the in vitro reconstitution of the cBAF, PBAF, and ncBAF complexes, and we compare their biochemical activities. In addition, we reconstitute a variety of cBAF subcomplexes, defining roles for several subunits in high affinity nucleosome binding and nucleosome sliding activity. Remarkably, we find that the ARID1A subunit of cBAF is largely dispensable for nucleosome binding, nucleosome sliding, and adenosine triphosphatase activity, but ARID1A is required for cBAF to transfer histone octamers between DNA templates. Our study reveals a biochemical function of ARID1A/ARID1B in BAF-mediated chromatin remodeling, suggesting a model in which dysregulation of histone octamer transfer activity of BAF complexes may be relevant to cancer formation.
Insights
Mutations in ARID1A, a subunit of SWI/SNF (or BAF) chromatin remodelers, are common in cancer. This study finds ARID1A is crucial for BAF complexes to transfer histone octamers, a key remodeling step.
Area of Science:
- Molecular Biology
- Cancer Genomics
- Chromatin Remodeling
Background:
- Mammalian SWI/SNF (mSWI/SNF or BAF) complexes are crucial for chromatin remodeling.
- Mutations in BAF subunits, particularly ARID1A, are prevalent in over 20% of human cancers.
- The precise biochemical role of ARID1A in BAF complex function remains unclear.
Purpose of the Study:
- To biochemically characterize the in vitro activity of reconstituted BAF complexes (cBAF, PBAF, ncBAF).
- To define the specific role of the ARID1A subunit in the catalytic and substrate-binding activities of the cBAF complex.
- To elucidate the function of ARID1A in chromatin remodeling.
Main Methods:
- In vitro reconstitution of cBAF, PBAF, and ncBAF complexes.
- Biochemical assays to measure nucleosome binding, nucleosome sliding, ATPase activity, and histone octamer transfer.
- Reconstitution of cBAF subcomplexes to dissect subunit functions.
Main Results:
- ARID1A is dispensable for nucleosome binding, nucleosome sliding, and ATPase activity of cBAF.
- ARID1A is essential for the cBAF complex to transfer histone octamers between DNA templates.
- ARID1A/ARID1B play a critical role in BAF-mediated chromatin remodeling via histone octamer transfer.
Conclusions:
- ARID1A has a distinct biochemical function in BAF complexes, specifically in histone octamer transfer.
- Dysregulation of ARID1A-mediated histone octamer transfer may contribute to cancer development.
- This finding provides a mechanistic link between ARID1A mutations and cancer pathogenesis.
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