# Non-transcriptional regulation of circadian physiology

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $380,140

## Abstract

Circadian clocks are endogenous protein machines that integrate external time cues and
internal metabolic states to regulate daily rhythms in physiology and behavior in organisms from
all kingdoms of life. In the natural world, environmental zeitgebers enable the animal circadian
clock to control timing of food intake. Nutrient influx can therefore provide metabolic signals to
reinforce environmental signals, promoting synchrony in circadian physiology to balance
metabolism and energy use. Initial efforts to dissect the underpinnings of the circadian oscillator
and its control over rhythms of life focused on regulation at the transcriptional level, as the core
oscillator proteins are transcription factors that collaborate to govern rhythmic expression of genes
involved in diverse cellular processes. More recent studies have uncovered complementary non-transcriptional mechanisms, including protein post-translational modifications (PTMs), that are
critical for circadian timekeeping. The overall goal of this project is to understand the
mechanisms by which metabolic and environmental signals integrate at the post-translational
level to regulate circadian physiology, and more importantly the consequences when these
signals that have evolved to cooperate are in conflict. We will use the diurnal Drosophila model
to test the central hypothesis that nutrient influx through clock-controlled feeding activity
regulates the interplay between phosphorylation and O-linked N-Acetylglucosaminylation (O-GlcNAcylation) of cellular proteins to modulate time-of-day specific functions. Protein O-GlcNAcylation is highly sensitive to metabolic input and may play a dominant role in extensive
remodeling of cellular protein functions, bypassing changes in gene expression. In Aim 1, we will
use time-restricted feeding (TRF) in combination with targeted metabolomics and
chemoenzymatic O-GlcNAc labeling to establish the relationships between feeding-fasting cycle,
nutrient influx, and O-GlcNAcylation status of cellular proteins. In Aim 2, we will identify cellular
proteins that exhibit daily interplay between O-GlcNAcylation and phosphorylation using label-free proteomic approaches. In Aim 3, we will characterize the function of clock protein O-GlcNAcylation events by utilizing tried-and-true molecular and Drosophila behavioral assays. By addressing the 3 questions: When, What, and Why, we will advance our understanding on
metabolic regulation of circadian physiology via post-translational mechanisms. This project will
have broad significance as cross-talk between protein phosphorylation and O-GlcNAcylation is
extensive and modulates a wide range of cellular processes. Our findings may identify new
therapeutic targets to alleviate circadian and metabolic disorders.

## Key facts

- **NIH application ID:** 10017211
- **Project number:** 5R01DK124068-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** JOANNA Chungyen CHIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,140
- **Award type:** 5
- **Project period:** 2019-09-11 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017211

## Citation

> US National Institutes of Health, RePORTER application 10017211, Non-transcriptional regulation of circadian physiology (5R01DK124068-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10017211. Licensed CC0.

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