# Genetic and Molecular Definition of Histone Modifying Enzyme Functions

> **NIH NIH R35** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $400,000

## Abstract

Understanding how histone modifications are regulated is fundamentally important for
understanding mechanisms of chromatin organization and gene regulation in both normal and
disease states. The overall goal of our research is to address this challenging question, using
genetic and molecular approaches to define which histone modifying enzymes, and by extension,
which histone modifications, govern specific gene expression programs in particular biological
contexts. Our work is focused largely on the Gcn5 histone acetyltransferase (HAT) and the
USP22 histone deubiquitylase (DUB), which are both components of a large multiprotein
assembly termed SAGA. Gcn5, USP22 and other SAGA components have been implicated in
human maladies, including cancer and neurodegeneration, but the molecular mechanisms
underlying such effects are not known. Over the past 20 years, we have created a novel toolkit
of Gcn5 and USP22 mutant mice and cells, including null alleles, conditional (floxed) alleles, and
point mutated alleles (in the Gcn5 HAT domain, the Gcn5 bromodomain, or the USP22 DUB
domain) that affect the activity of these enzymes. Our studies of Gcn5 mutations revealed key
insights to both transcriptional and non-transcriptional functions for this HAT during development,
and most recently, they revealed important connections between Gcn5 and Myc functions both in
normal stem cells and in cancer. Our USP22 mutant mice revealed that this DUB is also critical
for embryo survival, but through different pathways than those affected by Gcn5 loss. Despite
these advances, many significant gaps in knowledge still remain. We have only a partial view of
which transcription programs require Gcn5 in mammalian cells. Moreover, Gcn5 is now known
to be part of a second histone modifying complex called ATAC, but we do not know how Gcn5 is
apportioned between these complexes or their relative roles in development or disease. We also
have an incomplete understanding of the roles of USP22 and the SAGA DUB module in specific
tissues such as the cerebellum, which is especially relevant since specific components of the
SAGA DUB module are linked to a debilitating neurodegenerative disease, spinal cerebellar
ataxia type 7 (SCA7). This MIRA will provide us stable and flexible funding to continue our genetic,
biochemical, and molecular studies to address these critically important questions. In the longer
term, definition of the normal functions of Gcn5 and USP22 will provide molecular foundations for
development of new therapeutic options for diseases in which these factors are mis-regulated.

## Key facts

- **NIH application ID:** 10124409
- **Project number:** 5R35GM131678-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** SHARON Y. R. DENT
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $400,000
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124409

## Citation

> US National Institutes of Health, RePORTER application 10124409, Genetic and Molecular Definition of Histone Modifying Enzyme Functions (5R35GM131678-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124409. Licensed CC0.

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