# Mechanistic studies of chromatin modification in transcription regulation

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2024 · $946,600

## Abstract

PROJECT SUMMARY
Post-translational modifications of the histone proteins that package DNA play a central role in regulating
transcription and repair of DNA damage. The goal of this research program is to determine the molecular
mechanism by which attachment of the small protein, ubiquitin, to histone proteins functions in concert with
modifications including methylation and acetylation to regulate gene expression. Since misregulation of histone
ubiquitination and methylation characterizes many cancers, the results of these studies can be used to design
new drugs that target the molecular machines involved in these pathways. A major focus will be on the
mechanisms by which histone H2B-K120 monoubiquitination orchestrates multiple events during transcription
that result in gene activation. A multidisciplinary approach combining cryo-electron microscopy, x-ray
crystallography, solution biochemistry and cell-based approaches will be used to study the mechanism by
which ubiquitin is specifically attached to histone H2B during transcription and the distinct mechanisms by
which different deubiquitinating enzymes distinguish between H2B in intact versus partially disassembled
nucleosomes. We will also determine the nature of intra- and inter-nucleosomal cross-talk between histone
ubiquitination, methylation and acetylation mediated by transcriptional activators that act downstream of H2B
ubiquitination. Building upon the recent discovery of first-in-class macrocyclic inhibitors of the human SAGA
H2B deubiquitinating enzyme, we will determine their mechanism of action and derive principles that will drive
further drug discovery of multi-subunit deubiquitinating enzymes. To elucidate the molecular basis by which
H2B ubiquitination drives cell proliferation in MLL-rearranged leukeumia, we will uncover the role of histone
ubiquitination in stimulating the activity of MLL1 fusion complexes that result from chromosomal
rearrangements. The molecular insights that will result from the proposed studies will provide a foundation for
developing new chemotherapies that target cancers for which there currently are no effective treatments.

## Key facts

- **NIH application ID:** 10765278
- **Project number:** 2R35GM130393-06
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Cynthia Wolberger
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $946,600
- **Award type:** 2
- **Project period:** 2019-02-14 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765278

## Citation

> US National Institutes of Health, RePORTER application 10765278, Mechanistic studies of chromatin modification in transcription regulation (2R35GM130393-06). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10765278. Licensed CC0.

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