# Nutrient Regulation of Cell Physiology by O-GlcNAcylation

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2022 · $287,281

## Abstract

PROJECT SUMMARY
 The cycling of N-acetylglucosamine on Ser(Thr) residues (O-GlcNAcylation; OGN) on nuclear,
cytoplasmic and mitochondrial proteins serves as a nutrient sensor to regulate signaling,
transcription, and cellular physiology. Abnormal OGN underlies the etiology of diabetes, cancer
and Alzheimer's disease. OGN regulates nearly every aspect of transcription in response to
nutrients. Great strides have been made in developing methods that elucidate the functions of
OGN. While we can increase or decrease global OGN in cells, the greatest impediment toward a
mechanistic understanding of OGN's functions is the lack of a method to alter OGN on a single
protein without affecting the other thousands of OGN proteins within a cell.
 We discovered that the C-terminal domain of RNA polymerase II, which consists of 52
imperfect repeats of the sequence, YSPTSPS, is heavily OGN when it is not phosphorylated.
OGN of the CTD is required for transcription initiation, is reciprocal with phosphorylation, and the
sugar must be removed by O-GlcNAcase prior to elongation. While there have been many studies
of the role of phosphorylation of the CTD in transcription, in contrast, there have been no studies
of the specific roles of OGN on the CTD!
 We propose to develop an optogenetic approach to specifically target the O-GlcNAc
transferase (OGT) to specific proteins. Our plan is to adapt the LOV2 light-inducible dimer (iLID)
system. In this system, light-induced molecular association occurs on the sub-second time scale
and reversion in the dark can occur within ten minutes. Initially, we will use iLID to investigate the
roles of OGN in the insulin signaling pathway. OGT is normally targeted to its substrates by
accessory proteins, among which are TET proteins, enzymes that hydroxymethylate cytosine
residues, but also target OGT to chromatin. We will further investigate the roles of TET proteins
in OGT actions on chromatin, particularly on the CTD of Pol II. Finally, we will study the roles of
OGN on the CTD of RNA pol II in terms of its nutrient and stress responsiveness, and cell type
differences in sites modified. We will elucidate the interactome of OGN-CTD and we will determine
if OGN plays a role in RNA pol II pausing at promoters.
 These studies are not only elucidating molecular mechanisms of how nutrients regulate
transcription, but they also are key to revealing how hyperglycemia, as occurs in diabetes,
abnormally alters gene expression in many tissues. Molecular mechanisms revealed in these
studies will likely lead to totally novel targets for the treatment of chronic diseases of aging,
particularly diabetes.

## Key facts

- **NIH application ID:** 10458006
- **Project number:** 5R01GM116891-08
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** GERALD Warren HART
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $287,281
- **Award type:** 5
- **Project period:** 2016-08-10 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458006

## Citation

> US National Institutes of Health, RePORTER application 10458006, Nutrient Regulation of Cell Physiology by O-GlcNAcylation (5R01GM116891-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10458006. Licensed CC0.

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