# Molecular Mechanisms of Chromatin Recognition

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $461,304

## Abstract

PROJECT SUMMARY
The nucleosome is the fundamental unit of chromatin and a vibrant signaling hub for our genomes. Combinatorial
patterns of histone post-translational modifications (PTMs) and chemical modifications to DNA establish local
epigenetic landscapes that regulate genomic processes, including gene expression, replication, and DNA
damage repair. As genomic processes are critical to the maintenance of cellular identity and genomic integrity,
they are frequently misregulated in diverse diseases like cancer and developmental disorders. Despite clear
relevance to fundamental molecular biology and human health, the molecular mechanisms through which
histone PTMs are curated by nuclear enzymes that write and erase the PTMs in a nucleosome context are still
largely unknown. Moreover, outside of a small number of test cases, it is unclear how combinations of histone
PTMs recruit readers of histone PTMs to specific genomic loci. These knowledge gaps limit the development of
therapeutics targeting chromatin signaling for cancer or other diseases. We address these fundamental
questions using designer nucleosomes with chemically defined sets of histone PTMs which allow us to explore
how epigenetic signatures tune chromatin interactions proteome wide. In addition, to answering long-standing
questions about chromatin signaling, these nucleosome interactome screens uncover new biologic processes
that lead our research program in unexpected directions. In parallel, we solve near atomic resolution structures
of writers, readers, and erasers of histone PTMs bound to nucleosomes. These studies provide molecular
snapshots of the regulators of genomic processes in action in a physiologic chromatin context. Our structures
enable mechanistic hypothesis testing in cellular models with precision structure-guided mutations. Currently,
we are exploring how large multi-subunit complexes coordinate multiple enzymatic activities to regulate gene
expression by pairing structural biology with biochemistry, biophysics, cell biology, and genomics. Finally, we
are determining how the Anaphase Promoting Complex, a megadalton ubiquitin ligase that is a master regulator
of the cell cycle, functions on chromatin to control gene expression and histone homeostasis. Overall, we expect
to define universal patterns of chromatin recruitment through epigenetic landscapes and elucidate molecular
mechanisms through which chromatin proteins function to regulate gene expression and other genomic
processes. These studies will enable hypothesis-driven functional studies in disease model systems and uncover
new avenues for drug discovery.

## Key facts

- **NIH application ID:** 10842748
- **Project number:** 2R35GM133498-06
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Robert McGinty
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $461,304
- **Award type:** 2
- **Project period:** 2019-08-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842748

## Citation

> US National Institutes of Health, RePORTER application 10842748, Molecular Mechanisms of Chromatin Recognition (2R35GM133498-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10842748. Licensed CC0.

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