# Chemical Strategies to Investigate Gene Regulation By Histone Sumoylation

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $309,817

## Abstract

PROJECT SUMMARY
 The long-term goal of our proposed research is to elucidate the molecular mechanisms
underlying human gene regulation by histone H4 modification with the small ubiquitin-like
modifier-3 (SUMO-3) protein. Histone sumoylation is a dramatic post-translational
modification that occurs on the lysine12 side-chain in the unstructured N-terminal tail of
histone H4 (abbreviated as suH4). Early correlative studies in yeast and human cells
associated H4 tail sumoylation with reduced levels of histone H3 acetylation, and the
repression of gene transcription. However, the biochemical mechanisms by which histone
sumoylation may undertake gene repression remain unknown. Several human diseases,
including aggressive cancers of the blood and brain, are directly linked to the untimely
activation of gene transcription. Hence, by elucidating the molecular mechanisms
underlying transcription repression by histone sumoylation, we will identify new pathways
to predictably control gene function.
 Toward our goals, we developed chemical strategies to access site-specifically
sumoylated, methylated and acetylated histones. These histones were used in biophysical
and biochemical assays to reveal the direct effect of suH4 on chromatin structure and its
biochemical relationship with other modified histones. Our results, revealed that suH4
stimulates the demethylase and deacetylase activities of a key gene-silencing protein
complex responsible for silencing neuronal genes in non-neuronal cells. Furthermore,
when incorporated in place of H4, suH4 strongly inhibits transcription from chromatinized
templates. These exciting preliminary results set the stage for our proposed specific aims:
1. To investigate the mechanism of biochemical crosstalk between histone sumoylation,
methylation and acetylation. 2. To investigate the mechanism of transcription inhibition by
sumoylated H4. 3. To study gene regulation by sumoylated H4 in human cells.
 Success in these aims will elucidate the mechanistic underpinnings of suH4-mediated
gene repression in cells, and identify its biochemical crosstalk with two histone
modifications that are misregulated in several human diseases. Understanding suH4's
contribution to the function of multiple chromatin-regulating protein complexes will uncover
new targetable pathways to control misregulated genes.

## Key facts

- **NIH application ID:** 9850599
- **Project number:** 5R01GM110430-07
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Champak Chatterjee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $309,817
- **Award type:** 5
- **Project period:** 2014-05-05 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850599

## Citation

> US National Institutes of Health, RePORTER application 9850599, Chemical Strategies to Investigate Gene Regulation By Histone Sumoylation (5R01GM110430-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850599. Licensed CC0.

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