# Molecular mechanisms of histone signaling in a chromatin relevant context

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2020 · $381,709

## Abstract

Project Summary
The human genome exists in the cell nucleus as chromatin, a complex of the DNA with histone proteins.
Though genetic information is encoded in the DNA sequence, another layer of information, is encoded in the
histone proteins, specifically in the form of post-translational modifications (PTMs). This layer of information is
often referred to as epigenetics, and provides instructions on how the genome is to be regulated. Chromatin
and the epigenetic content, is highly dynamic, constantly restructuring in response to developmental and
environmental cues. One of the most important questions in biology is how this information is interpreted by
transcriptional and other regulatory complexes, leading to gene regulation and cell fate. Histone modifications
are “read” through small subdomains within the regulatory complexes called reader domains, and specificity for
a unique modification state is thought to be achieved through the integrated activity of multiples of these
domains. However, though much is known about the association of reader domains with fragments of histones,
the molecular mechanims underlying how they associate with histones in a chromatin relevent context, or how
they function together to readout a specific histone modification state, are not well understood. This research
program addresses this fundamental question in chromatin regulation. We are pioneering the use of NMR
spectroscopy to study the association of reader domains with the basic unit of chromatin, the nucleosome. We
are combining this with X-ray crystallography, fluorescence spectroscopy, biolayer interferometry, and basic
biochemistry for an overall multidisciplinary approach to building models of these complexes. Over the next five
years we will determine the thermodynamic and structural basis of association of reader domains from the BAF
chromatin remodeling and Polycomb histone modifying complexes with nucleosomes, the influence of adjacent
chromatin binding domains, and the functional consequence of these interactions. Long-term, we will build
towards an understand of how multiple reader domains in these complexes integrate to allow these regulatory
complexes to navigate and respond to a dynamic chromatin substrate. The results of these studies will reveal
fundamental mechanisms of chromatin regulation, provide insight into the etiology of a number of human
diseases, and lay the groundwork for the development of targeted therapeutics.

## Key facts

- **NIH application ID:** 10000110
- **Project number:** 5R35GM128705-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Catherine Anne Musselman
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,709
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000110

## Citation

> US National Institutes of Health, RePORTER application 10000110, Molecular mechanisms of histone signaling in a chromatin relevant context (5R35GM128705-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000110. Licensed CC0.

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