# Nutrient-sensitive protein modifications regulate daily biological rhythms

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $241,500

## Abstract

PROJECT SUMMARY
Robust daily biological rhythms over the 24-hour (h) day-night cycles are key hallmarks of animal
healthspan and are strongly regulated by circadian clocks. Circadian clocks are cell-autonomous,
endogenous molecular timers present in the brain and peripheral organs that enable animals to adapt to daily
changes in their environment. Clock-controlled outputs are all-encompassing and clock disruption is
associated with a wide range of pathologies and chronic diseases. While the brain clock is synchronized to
external environment via photic cues from light-dark cycles, peripheral clocks in major organs are entrained
and synchronized by metabolic signals mediated primarily via food intake that are regulated by the brain clock.
This coupled brain and peripheral clock system promotes internal synchrony, maintaining balance between
metabolism and energy use. Given the importance of metabolic signals in regulating body clocks, it is critical
to understand mechanisms underlying metabolic regulation of daily biological rhythms. The overall goal of
this project is to investigate post-translational mechanisms that mediate metabolic regulation of time-of-day
protein functions to orchestrate daily rhythms. Efforts to understand the underpinnings of circadian clocks and
their control over daily rhythms have long focused on regulation at the transcriptional level. However, recent
studies have demonstrably confirmed the importance of post-translational modifications (PTMs) in shaping
robust daily rhythms, often bypassing regulation at the gene expression level. We recently established that
metabolic signals from feeding-fasting cycles drive robust daily rhythms of global O-GlcNAcylation in
Drosophila and in mouse peripheral tissues. O-GlcNAcylation is a nutrient-sensitive PTM that interacts
extensively with phosphorylation to regulate protein structure and function as both PTMs modify serine and
threonine residues. We will test the hypothesis that rhythmic O-GlcNAcylation and phosphorylation work in
conjunction to regulate daily rhythms of protein activities. We further test the hypothesis that altering timing
of metabolic input by mistimed feeding will remodel the O-GlcNAcome, phosphoproteome, and their
interactions, resulting in potential disruption of peripheral clock functions. To date, there have only been a
handful of studies investigating rhythmic O-GlcNAcylation and the consequences of its disruption. This project
is designed to address this significant knowledge gap. In Aim 1, we will identify proteins that are rhythmically
modified by O-GlcNAcylation and phosphorylation in key mammalian organs and investigate whether and to
what extent rhythmic PTM profiles are sensitive to timing of metabolic input. In Aim 2, we will incorporate
proteomics data generated from this project into O-GlcNAc Atlas, a searchable database with a web interface
constructed by our collaborator Dr. Junfeng Ma, to enable user-friendly data discovery. This R21 project...

## Key facts

- **NIH application ID:** 10826071
- **Project number:** 1R21AG082480-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** JOANNA Chungyen CHIU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $241,500
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10826071

## Citation

> US National Institutes of Health, RePORTER application 10826071, Nutrient-sensitive protein modifications regulate daily biological rhythms (1R21AG082480-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10826071. Licensed CC0.

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