# Molecular mechanisms of histone modification

> **NIH NIH R37** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $341,677

## Abstract

Enzyme-catalyzed histone modifications (e.g. (de)acetylation, (de)phosphorylation, and (de)methylation)
result in a unique set of chemical 'marks' that regulate chromatin function through mechanisms that remain a
focus of intense study. The combinatorial nature of these posttranslational modifications (PTMs) give rise to
a histone 'code' or 'language', which is interpreted by enzyme complexes to mediate transcriptional
responses. Importantly, these chromatin-modifying complexes have evolved to use co-substrates that are
major metabolites linked to essential metabolic pathways, a fact eliciting the possibility that chromatin
modifying enzymes exquisitely 'sense' metabolite levels (like acetyl-CoA, NAD+, SAM, 02, α-KG.) and
respond accordingly, modifying specific chromatin loci for the appropriate response in gene expression. This
proposal will investigate how metabolism and key epi-metabolite levels regulates epigenetic programs by
controlling the activity of specific acetyltransferases, deacetylases, methyltransferases, and demethylases. In
this proposal, we will investigate the hypothesis that epi-metabolite levels and the metabolic enzymes that
produce these are intimately connected to chromatin modifying enzymes and that this link is a fundamental
regulatory mechanism for controlling specific gene expression programs. To accomplish these goals, three
aims are proposed: 1.) to determine how short-chain fatty acids produced from gut microbiota affect
epigenetic control of gene expression in the host, 2) to determine the role of nuclear acetyl-CoA synthetase
in controlling histone and non-histone protein acetylation, and 3.) to elucidate how SAM (S-adenosyl
methionine) synthesis in the nucleus leads to maintenance of repressive epigenetic marks during metabolic
stress. These integrated studies will provide a deep molecular understanding of the connections between
metabolites acetyl-CoA and S-adenosyl methionine, and the dynamic regulation of chromatin modifications
(acetylation and methylation) that drive both normal and stress-response pathways of gene expression.

## Key facts

- **NIH application ID:** 9978816
- **Project number:** 5R37GM059785-22
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** JOHN M DENU
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $341,677
- **Award type:** 5
- **Project period:** 1999-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978816

## Citation

> US National Institutes of Health, RePORTER application 9978816, Molecular mechanisms of histone modification (5R37GM059785-22). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9978816. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*