# Mechanisms of circadian clock and codon usage biases

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $167,197

## Abstract

Abstract
 This proposal will be focused on the understanding of mechanisms of two fundamental
biological phenomena in eukaryotes: the circadian clock and codon usage bias. Circadian
clocks control diverse cellular, physiological, and behavioral processes in eukaryotic organisms.
Our long-term goal is to understand the molecular and biochemical mechanisms that permit the
measurement of time and the output of circadian rhythms in eukaryotic circadian clocks. Our
previous studies made fundamental contributions to the understanding of the eukaryotic
circadian clock mechanisms. Synonymous codons are not used with equal frequencies in all
genomes examined, a phenomenon called codon usage bias. Even though the phenomenon of
codon usage bias has been known for several decades, the functions and mechanisms of
codon usage bias are unclear. Our previous work demonstrate that codon usage is a novel layer
of the genetic code that can determine both gene expression levels and protein structures. Our
lab uses Neurospora, Drosophila and mammalian systems to study these two phenomena.
 For the circadian clock project, we propose to focus on several key aspects of the
circadian oscillator mechanism in both Neurospora and mammalian clock systems. We will
determine the role and mechanism of FRQ-CK1a interaction in circadian period determination in
Neurospora. In addition, we will expand our study into a mammalian system by determining the
role of the PERIOD-CK1 interaction in the mammalian circadian clock. These studies will
establish a conserved mechanism for period determination in fungi and animals. Although FRQ
in Neurospora and PER proteins in animals are not considered homologous, most of the
domains in both proteins are predicted to be intrinsically disordered and both are progressively
phosphorylated. We will determine how FRQ and PER function in the circadian clock using
biochemical and molecular methods. For the codon usage project, we will build on our ground-
breaking discoveries on the roles and mechanisms of codon usage biases in determining gene
expression and protein structures. We will determine the mechanism of the codon usage effect
on gene transcription in Neurospora based on a previously performed large-scale genetic
screen. This study will reveal the mechanisms that underlie the conserved effect of codon usage
on gene transcription. We will evaluate how codon usage influences gene expression in mice by
creating an in vivo codon usage reporter. This study will establish the mechanism that
contributes to effects of codon usage on tissue- and cell type-specific gene expression in
mammals. In addition, we will develop a method to modulate translation elongation speed based
on the role of codon usage in regulating protein folding that will have potential for use in
treatment of many diseases. Together, these studies will address fundamental questions that
are critical for our understanding of these two biological phenomena in eukaryotes.

## Key facts

- **NIH application ID:** 11098380
- **Project number:** 3R35GM118118-09S1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** YI LIU
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $167,197
- **Award type:** 3
- **Project period:** 2016-04-04 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11098380

## Citation

> US National Institutes of Health, RePORTER application 11098380, Mechanisms of circadian clock and codon usage biases (3R35GM118118-09S1). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/11098380. Licensed CC0.

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