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Updated: Apr 21, 2026
Analyzing Oxidative Stress in Murine Intestinal Organoids using Reactive Oxygen Species-Sensitive Fluorogenic Probe
Published on: September 17, 2021
KDM5 interacts with Foxo to modulate cellular levels of oxidative stress
Xingyin Liu1, Christina Greer1, Julie Secombe1
1Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
Abstract:
Increased cellular levels of oxidative stress are implicated in a large number of human diseases. Here we describe the transcription co-factor KDM5 (also known as Lid) as a new critical regulator of cellular redox state. Moreover, this occurs through a novel KDM5 activity whereby it alters the ability of the transcription factor Foxo to bind to DNA. Our microarray analyses of kdm5 mutants revealed a striking enrichment for genes required to regulate cellular levels of oxidative stress. Consistent with this, loss of kdm5 results in increased sensitivity to treatment with oxidizers, elevated levels of oxidized proteins, and increased mutation load. KDM5 activates oxidative stress resistance genes by interacting with Foxo to facilitate its recruitment to KDM5-Foxo co-regulated genes. Significantly, this occurs independently of KDM5's well-characterized demethylase activity. Instead, KDM5 interacts with the lysine deacetylase HDAC4 to promote Foxo deacetylation, which affects Foxo DNA binding.
Insights
The transcription co-factor KDM5 regulates cellular redox state by altering Foxo DNA binding, independent of its demethylase activity. This novel function is crucial for managing oxidative stress and preventing disease.
Area of Science:
- Cellular Biology
- Molecular Biology
- Genetics
Background:
- Oxidative stress is linked to numerous human diseases.
- Identifying key regulators of cellular redox state is critical for understanding disease mechanisms.
Purpose of the Study:
- To identify novel regulators of cellular redox state.
- To elucidate the mechanism by which KDM5 influences oxidative stress resistance.
Main Methods:
- Microarray analysis of kdm5 mutants.
- Assessing sensitivity to oxidizers and levels of oxidized proteins.
- Investigating protein-protein interactions between KDM5, Foxo, and HDAC4.
Main Results:
- KDM5 (also known as Lid) is identified as a critical regulator of cellular redox state.
- KDM5 alters Foxo transcription factor's DNA binding ability through interaction with HDAC4.
- Loss of kdm5 leads to increased sensitivity to oxidizers, elevated oxidized proteins, and higher mutation load.
- KDM5 activates oxidative stress resistance genes via Foxo, independently of its demethylase activity.
Conclusions:
- KDM5 plays a novel role in regulating cellular oxidative stress response.
- This function is mediated by KDM5's interaction with HDAC4 to deacetylate Foxo, thereby affecting its DNA binding.
- Understanding this pathway offers potential therapeutic targets for diseases associated with oxidative stress.
