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5hmC modification regulates R-loop accumulation in response to stress
Xingyun Xu1,2, Junjie Wang2, Wenjuan Wang2
1Department of Neurology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
Frontiers in Psychiatry
|June 26, 2023
Summary
Chronic stress increases R-loops, DNA damage, and genomic instability. DNA 5-hydroxymethylcytosine (5hmC) modification, via the NONO-Tet complex, negatively regulates R-loops, offering potential therapeutic targets for depression.
Area of Science:
- Epigenetics
- Neuroscience
- Genomics
Background:
- R-loops, RNA-DNA hybrids, are transcriptional by-products linked to DNA damage and genomic instability.
- Ten-eleven translocation (Tet) proteins modify DNA by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC).
- The precise relationship between R-loops and 5hmC modification remains largely undefined.
Purpose of the Study:
- To investigate the regulatory role of DNA 5hmC modification in R-loop accumulation under stress.
- To elucidate the molecular mechanisms, including protein interactions, underlying R-loop regulation.
- To identify potential therapeutic targets for stress-induced neurological conditions.
Main Methods:
- Analysis of R-loop and 5hmC levels in mouse prefrontal cortex (PFC) under chronic restraint stress.
- Pharmacological manipulation of 5hmC levels using vitamin C and compound SC-1.
- Investigation of Tet and NONO protein interactions and their role in R-loop formation using immunoprecipitation and gene silencing.
- Assessment of DNA damage and therapeutic efficacy of fluoxetine in stressed mice.
Main Results:
- Chronic stress increased R-loop accumulation and decreased 5hmC levels in the PFC.
- Elevating 5hmC reduced R-loops, while decreasing 5hmC increased R-loops, confirming an inverse relationship.
- Tet proteins and NONO form a complex that inhibits R-loop formation; deficiency in either protein increased R-loops.
- NONO protein levels decreased in stressed mice; fluoxetine treatment restored NONO, reduced R-loops, and mitigated DNA damage.
Conclusions:
- DNA 5hmC modification negatively regulates R-loop accumulation through the NONO-Tet complex under stress.
- NONO protein levels are reduced by stress, contributing to R-loop accumulation.
- Targeting the NONO-Tet complex and 5hmC modification presents a promising therapeutic strategy for depression.
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