# Epigenetic regulation of embryonic stem cells by ATP-dependent BAF chromatin remodeling complexes

> **NIH NIH R35** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2021 · $481,000

## Abstract

PROJECT SUMMARY
Self-renewal and pluripotency are defining properties of an embryonic stem cell (ESC). Although extremely
transient in vivo, these cells can be captured from the inner cell mass of the embryo and maintained indefinitely
in a pluripotent state or differentiated into essentially any specialized cell in vitro. As such, embryonic stem
cells (ESCs) hold great promise for regenerative medicine, which seeks to use ESCs to regenerate or
rejuvenate cells and tissues that have been damaged due to injury, disease, or underlying genetic mutations.
However, to leverage their full potential, we must understand the mechanisms that control ESC self-renewal
and pluriptency to allow (re)generation of any tissue while preventing aberrant growth or depletion of the stem
cell pool. Stem cell identity is defined by a gene regulatory network dictated by the master regulators OCT4,
SOX2 and NANOG. However, the binding of these transcriptional factors is in turn highly dependent on the
accessibility of the chromatin landscape. To access the underlying genomic information, histone proteins must
be repositioned or removed, a function that is performed by ATP-dependent chromatin remodeling complexes.
In particular, several components of the mammalian SWI/SNF or BAF complex are essential for formation of
the inner cell mass and for derivation of ESCs in vitro. BAF complexes are regulated by the combinatorial
assembly of homologous subunits from gene families. However, there is currently no mechanistic
understanding of how unique combinations of distinct subunits affect BAF complex targeting or function. Using
biochemical approaches, a completely novel and previously undescribed form of the BAF complex was
discovered in ESCs that contains the acetyl lysine reader, Bromodomain-containing protein 9 (BRD9). Due to
the incorporation of BRD9 and other unique subunits, the BRD9-containing BAF complex or 'BBAF complex' is
uniquely targeted across the genome and exhibits specific regulatory interactions not found associated with
canonical BAF complexes. Moreover, the BBAF complex lacks certain subunits that are critical for ATP-
dependent chromatin remodeling, suggesting that it may have alternate function. The goals for the next five
years are to determine the mechanism of BRD9-mediated chromatin targeting of the BBAF complex and how
that relates to the transcriptional regulation of genes involved in ESC self-renewal and pluripotency. These
studies will aid in our understanding of how BAF complex heterogeneity contributes to the precise control of
the ESC transcriptional program and provide a framework for understanding the roles of individual BAF
subunits in contributing to cell type- and developmental stage-specific function of BAF complexes.

## Key facts

- **NIH application ID:** 10226169
- **Project number:** 5R35GM128943-04
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Diana Clare Hargreaves
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $481,000
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226169

## Citation

> US National Institutes of Health, RePORTER application 10226169, Epigenetic regulation of embryonic stem cells by ATP-dependent BAF chromatin remodeling complexes (5R35GM128943-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10226169. Licensed CC0.

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