# Genome-wide mechanisms and dynamics of ATP-dependent chromatin remodeling complexes

> **NIH NIH K99** · FRED HUTCHINSON CANCER CENTER · 2022 · $99,999

## Abstract

PROJECT SUMMARY/ABSTRACT
 The SWI/SNF family ATP-dependent chromatin remodelers are multi-subunit protein complexes that
dynamically position chromosomal nucleosomes to modulate DNA accessibility, transcription-factor binding,
and cell-type-specific gene expression. SWI/SNF function is crucial at several stages of mammalian
development, and recent human whole-genome and exome sequencing studies revealed striking mutational
frequencies in genes encoding SWI/SNF subunits across a range of diseases - from neurologic disorders to
over 20% of all cancers. Disease-associated SWI/SNF mutations often cause the loss of a protein subunit that
further destabilizes the complex and results in altered subunit composition and functions. Of note,
heterogeneity in SWI/SNF subunit composition is also observed naturally within and across cell types,
hypothesized to result in complex- and tissue-specific SWI/SNF functions. Despite their importance, how these
subunits determine the substrate preference and mechanistic functions of SWI/SNF complexes are not well
understood, largely due to the lack of robust approaches to characterize where they bind within the genome
and how they interact with chromatin genome-wide. Thus, the main goal of this proposal is to address this key
knowledge gap. Since chromatin remodelers directly interact with nucleosomes, it is important to clarify
remodeler-bound nucleosome compositions and structures. Standard biochemical characterization of soluble
components purified from cellular extracts cannot determine the nucleosome structures associated with
chromatin-bound complexes. It is also important to understand the kinetic parameters of remodeler-chromatin
interactions, such as how fast a remodeler is recruited to its target sites, and how long does it remain bound at
its genomic sites. The candidate proposes to address these questions by using structural and functional
epigenomics approaches and live-cell single-molecule imaging, to characterize remodeler-chromatin
interactions in the context of the complex and dynamic chromatin environment inside cells. Aim 1 is to
determine the genome-wide occupancy of SWI/SNF complexes with distinct subunit compositions. Aim 2 is to
determine a) the structures and histone composition of remodeler-bound nucleosomes genome-wide, and b)
the kinetic parameters of remodeler-chromatin interactions in live cells. Aim 3 is to study the interaction of
SWI/SNF with repressive chromatin. The mentored phase of this project will be completed under the
sponsorship of Dr. Steven Henikoff at the Fred Hutchinson Cancer Research Center. The candidate will
acquire training in live-cell single-molecule imaging under the supervision of Dr. Sheila Teves at the University
of British Columbia. The proposed research and training will provide a strong foundation for the candidate to
develop as an independent investigator, studying chromatin remodeling mechanisms and dynamics in the
regulation of fundamental cellular processes...

## Key facts

- **NIH application ID:** 10371166
- **Project number:** 6K99GM138920-02
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Sandipan Brahma
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $99,999
- **Award type:** 6
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371166

## Citation

> US National Institutes of Health, RePORTER application 10371166, Genome-wide mechanisms and dynamics of ATP-dependent chromatin remodeling complexes (6K99GM138920-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10371166. Licensed CC0.

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