# Structural and Functional Characterization of the Chd1 Chromatin Remodeler

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $415,184

## Abstract

ABSTRACT
 Chromatin remodelers are ATP-dependent DNA translocases that catalyze disassembly, reassembly, and
repositioning of nucleosomes throughout eukaryotic genomes. As evidenced from multiple types of cancer and
developmental disorders associated with remodeler mutations, chromatin remodeling is essential for normal
growth and development. This proposal aims to address core mechanistic questions of remodeler action and
regulation, using the Chd1 chromatin remodeler as a model system. Recent studies revealed that chromatin
remodelers shift nucleosomes using a twist defect mechanism. In this process, remodelers couple distinct
nucleotide-dependent conformations of the ATPase motor to create and then eliminate DNA distortions (twist
defects) that stimulate the nucleosome to transiently absorb and then release an extra bp at the remodeler
binding site. Currently, it is unknown how remodelers create twist defects. Aim 1 of this proposal seeks to
identify key residues and elements of Chd1 necessary for distorting DNA into twist defects, which should allow
for a mechanistic understanding of this central process. Another question addressed by this proposal is how
remodeler ATPases are regulated. For Chd1, nucleosome sliding activity is coupled to DNA outside the
nucleosome, with a requirement for flanking DNA on the “entry” side and preference for little or no DNA on the
“exit” side. For Chd1, flanking DNA controls sliding activity through a DNA-binding domain that is coupled to
autoinhibitory elements. A central question addressed by Aim 2 of this proposal is how stability and interactions
of autoinhibitory elements are controlled by distinct domain arrangements on the nucleosome. Experiments are
designed to reveal kinetic transitions of remodeler rearrangements on the nucleosome. Finally, a major
unanswered question is how two remodelers bound to the same nucleosome affect activity of each other. Chd1
has been shown to bind to nucleosomes in a 2:1 ratio, with the DNA-binding domain interacting in trans with
the chromo-ATPase, yet the significance of these interactions is unknown. Aim 3 tests the hypothesis that two
opposing remodelers bound to the same nucleosome antagonize each other. Together, these studies will
provide new mechanistic insights into how remodelers alter nucleosome structure, autoregulate action of their
central ATPase motor, and coordinate and potentially control other remodelers on the nucleosome.

## Key facts

- **NIH application ID:** 10814794
- **Project number:** 5R01GM084192-17
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** GREGORY DEAN BOWMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $415,184
- **Award type:** 5
- **Project period:** 2008-04-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814794

## Citation

> US National Institutes of Health, RePORTER application 10814794, Structural and Functional Characterization of the Chd1 Chromatin Remodeler (5R01GM084192-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10814794. Licensed CC0.

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