# Regulation of Rhythmic m6A RNA Modification by ER‐associated Degradation

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2024 · $503,374

## Abstract

Endoplasmic Reticulum (ER)-Associated Degradation (ERAD) is a major ER quality-control program that
monitors and translocates unfolded or misfolded protein substrates from the ER to cytosol for polyubiquitination
and proteasomal degradation. N6-methyladenosine (m6A) methylation, the most prevalent internal modification
of mammalian mRNAs, is known to regulate the stability, translation, and function of almost every major class of
human RNAs. Three major families of proteins, including writers, readers, and erasers, are known to be
responsible for the reversible RNA m6A methylation process. However, the signal transduction pathway
underlying the regulation of RNA m6A modification remain elusive. Herein, we accumulated strong preliminary
evidence for an unprecedented circadian-regulated ERAD pathway that controls mRNA m6A modification and
subsequent lipid homeostasis, which we called “circadian ERAD-m6A”. Our major preliminary findings include:
(i) the ER-resident E3 ubiquitin ligase HRD1 and its co-factor SEL1L, the major components of ERAD machinery,
are regulated by the circadian clock in the liver; (ii) HRD1 interacts with and mediates polyubiquitination and
degradation of the specific m6A writer METTL14 and the reader YTHDF3; (iii) HRD1 liver-specific KO (LKO)
mice display reversed fashions with METTL14-LKO or YTHDF3-knockdown mice in hepatic m6A mRNA
methylation levels, expression of lipid metabolic regulators, and metabolic phenotypes associated with hepatic
steatosis and hyperlipidemia; and (iv) unlike the classic ERAD, the newly-identified ERAD-m6A regulatory axis
and its function in hepatic lipid metabolism are under the control of circadian rhythm. These observations led to
our central hypothesis that the liver HRD1-ERAD program, which is oscillated under the circadian clock,
regulates hepatic m6A RNA modification by controlling rhythmic degradation of the specific m6A writer METTL14
and the reader YTHDF3. This unprecedented circadian ERAD-m6A RNA modification regulatory network, which
may be dysregulated by circadian-disrupting cues, represents a major pathway that controls metabolic
homeostasis associated with hepatic steatosis and hyperlipidemia.
 In this application, we will utilize molecular and cellular approaches, genetically engineered animal models,
and high-throughput profiling of m6A RNA modification to critically address the function and mechanism by which
circadian ERAD regulates hepatic m6A RNA modification and lipid metabolism. In two aims, we will: 1) define a
novel circadian ERAD pathway that modulates rhythmic m6A RNA modification through degrading the specific
m6A writer and reader; and 2) determine the functional significance of circadian ERAD-m6A RNA modification
pathway in maintaining lipid homeostasis. Upon completion of this project, we will reveal the function and
mechanism by which a novel circadian ERAD-m6A RNA modification pathway regulates lipid homeostasis
associated with metabolic disorders. The findings wi...

## Key facts

- **NIH application ID:** 10831980
- **Project number:** 5R01DK126908-04
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Deyu Fang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $503,374
- **Award type:** 5
- **Project period:** 2021-07-16 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831980

## Citation

> US National Institutes of Health, RePORTER application 10831980, Regulation of Rhythmic m6A RNA Modification by ER‐associated Degradation (5R01DK126908-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10831980. Licensed CC0.

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