# Dysregulation of BAF chromatin remodeling in cancer

> **NIH NIH F30** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $51,036

## Abstract

Project Summary/Abstract
Epigenetic dysregulation is a major driver of tumorigenesis. The most commonly mutated epigenetic modifier in
human cancer is the BAF complex (Brahma Associated Factors). BAF is an evolutionarily-conserved multi-
subunit ATP-dependent chromatin remodeling complex that is mutated in one fifth of all cancers. BAF
mobilizes nucleosomes to expose the underlying DNA in order to regulate access of DNA binding sites to
transcriptional machinery, and thus functions as a major regulator of transcription. The enzymatic activity of the
complex is provided by one of two mutually exclusive catalytic ATPases, BRG1 or BRM, with additional
subunits regulating the targeting and enzymatic activity of the complex. Despite the frequency of BAF
mutations in cancer, little is known about how cancer-associated BAF mutations affect the nucleosome
remodeling activity of the complex or contribute to tumorigenesis. Determining the effects of these mutations is
hindered by our lack of knowledge regarding the normal activity and regulation of the complex. This study will
address this gap in knowledge by using purified recombinant BAF complexes to assess the normal regulation
of the complex as well as its misregulation in cancer. This study will leverage the known regulatory features of
RSC, a yeast homolog of BAF, and test whether they are conserved in humans. The function of the
Actin/BAF53 module as well as the roles of the Post-HSA and Protrusion 1 domains of BRG1 and BRM in the
catalytic activity of the complex will be assessed. The Post-HSA and Protrusion 1 domains of BRG1 and BRM
are frequently mutated in cancer; the effects of these mutations on the remodeling activity of the complex will
be examined as well. The most clearly oncogenic BAF alterations are the uniform loss of the SNF5 subunit in
malignant rhabdoid tumor (MRT) and the fusion between the SS18 BAF subunit and the SSX protein in
synovial sarcoma (SS), which is reported to evict SNF5 from the BAF complex. MRT and SS are among the
most genetically simple tumors, each typically bearing only the single genetic alteration listed above. This lack
of additional mutations suggests that SNF5 loss and the SS18-SSX fusion protein promote tumor formation
through an epigenetic mechanism. Importantly, SNF5 affects the catalytic activity of BRG1, suggesting that
aberrant enzymatic activity of the complex is the epigenetic driver of tumorigenesis in MRT and SS. The tumor
specificity of these mutations indicates that SS18-SSX fusions and SNF5 loss are not equivalent. The
nucleosome remodeling activities of recombinant BAF complexes containing or lacking SNF5 and SS18-SSX
fusions will be assessed to determine whether the tissue specificity of these mutations may be attributed to a
difference in catalytic activity. The results of this study will provide insight into the normal function of a major
epigenetic modifier as well as its misregulation in cancer, and may inform new therapeutic strategies in ...

## Key facts

- **NIH application ID:** 10216198
- **Project number:** 5F30CA225163-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Timothy Mulvihill
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216198

## Citation

> US National Institutes of Health, RePORTER application 10216198, Dysregulation of BAF chromatin remodeling in cancer (5F30CA225163-04). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10216198. Licensed CC0.

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