# The role of BAF related complexes in regulatory T cell development and function

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $792,780

## Abstract

PROJECT SUMMARY
Regulatory T cells (Treg) play a crucial role in keeping the immune system in balance and preventing
autoimmune disease. Defective Treg function leads to autoimmune diseases including rheumatoid arthritis and
multiple sclerosis. On the other hand, Treg cells inside tumors can block effective anti-tumor immune responses.
The development and maintenance of the Treg cell lineage are dependent on the transcription factor Foxp3, as
loss of function mutations lead to severe lymphoproliferative disease in mice and humans. Thus, understanding
the mechanisms that govern Foxp3 induction and stability may lead to the development of novel therapies for
autoimmune disease and cancer. Dr. Zheng and colleagues recently developed a system to perform genome-
wide CRISPR/Cas9 knockout screens to identify Foxp3 regulators in mouse induced and natural Tregs. The
unbiased screen results not only confirmed a number of known Foxp3 regulators but also revealed many novel
factors that control Foxp3 expression. Gene ontology analysis of the newly identified Foxp3 regulators revealed
significant enrichment of multiple genes encoding subunits of the BAF (SWI/SNF) chromatin remodeling
complexes, indicating an unknown role for this regulator in Treg development. Among the three BAF related
complexes, the newly described GBAF complex promotes the expression of Foxp3, whereas the PBAF complex
represses its expression. Furthermore, deletion of the bromodomain-containing protein Brd9, specific to GBAF
complexes, led to reduced Foxp3 expression and compromised Treg function. Additionally, bromodomain
inhibitors and chemical degraders of BRD9 act similarly to Brd9 genetic deletion to impair Foxp3 expression and
Treg suppressor function. RNA-seq and ChIP-seq studies suggest that Brd9 cooperates with Foxp3 to potentiate
its binding to Foxp3 target genes and regulate their expression. The overall objective of this study is to define
the role of BAF related complexes in Treg function through regulation of and cooperation with Foxp3. This goal
will be accomplished by elucidating the role of G/PBAF in Foxp3 induction and maintenance (Aim 1), defining
the biochemical association of G/PBAF complexes with Foxp3 (Aim 2), identifying the functional role of GBAF in
Foxp3-dependent transcription (Aim 3), and characterizing the functional consequences of disrupting G/PBAF
subunits in Tregs in autoimmune disease and cancer models (Aim 4). The outcomes of the proposed studies
are expected to fundamentally advance the understanding of epigenetic control of Foxp3 gene expression and
Treg transcriptional networks. Additionally, these studies will provide key insights into the function of the newly
described GBAF complex and its relationship with PBAF complexes. Finally, the outcomes of this research could
provide evidence to support using drugs to target BAF related complexes for the treatment of autoimmune
diseases and cancer.

## Key facts

- **NIH application ID:** 10073371
- **Project number:** 1R01AI151123-01A1
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Diana Clare Hargreaves
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $792,780
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073371

## Citation

> US National Institutes of Health, RePORTER application 10073371, The role of BAF related complexes in regulatory T cell development and function (1R01AI151123-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073371. Licensed CC0.

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