Decitabine improves MMS-induced retinal photoreceptor cell damage by targeting DNMT3A and DNMT3B
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Updated: Aug 12, 2025
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
Yanli Ji1,2, Meng Zhao1,2, Xiaomeng Qiao3
1Laboratory of Visual Cell Differentiation and Regulation, Basic Medical College, Zhengzhou University, Zhengzhou, China.
Introduction:
Retinitis pigmentosa (RP) is a group of neurodegenerative retinopathies causing blindness due to progressive and irreversible photoreceptor cell death. The alkylating agent methyl methanesulfonate (MMS) can induce selective photoreceptor cell death, which is used to establish RP animal models. MMS induces DNA base damage by adding alkyl groups to DNA, and epigenetic modifications influence DNA damage response. Here, we aimed to explore the relationship between DNA methylation and DNA damage response in dying photoreceptors of RP.
Methods:
The mouse RP model was established by a single intraperitoneal injection of MMS. The retinal structure and function were assessed by H&E, OCT, TUNEL, and ERG at several time points. The expression of DNA methylation regulators was assessed by qPCR and Western blot. DNMT inhibitor 5-aza-dC was applied to inhibit the activity of DNA methyltransferases and improve the retinal photoreceptor damage.
Results:
The outer nuclear layer (ONL) and IS/OS layer were significantly thinner and the retinal function was impaired after MMS treatment. The cell death was mainly located in the ONL. The retinal damage induced by MMS was accompanied by hyperexpression of DNMT3A/3B. The application of DNMT inhibitor 5-aza-dC could suppress the expression level of DNMT3A/3B, resulting in the remission of MMS-induced photoreceptor cell damage. The ONL and IS/OS layers were thicker than that of the control group, and the retinal function was partially restored. This protective effect of 5-aza-dC was associated with the down-regulated expression of DNMT3A/3B.
Conclusion:
These findings identified a functional role of DNMT3A/3B in MMS-induced photoreceptor cell damage and provided novel evidence to support DNMTs as potential therapeutic targets in retinal degenerative diseases.Graphical Abstract.
Insights
Methyl methanesulfonate (MMS) causes photoreceptor cell death in retinitis pigmentosa (RP) models. Inhibiting DNA methyltransferases (DNMTs) with 5-aza-dC protected photoreceptors and improved retinal function by suppressing DNMT3A/3B expression.
Area of Science:
- Neuroscience
- Genetics
- Ophthalmology
Background:
- Retinitis pigmentosa (RP) is a group of inherited retinal diseases characterized by progressive photoreceptor degeneration and blindness.
- Methyl methanesulfonate (MMS) is an alkylating agent used to induce photoreceptor cell death in animal models of RP.
- Epigenetic modifications, particularly DNA methylation, play a role in DNA damage response pathways.
Purpose of the Study:
- To investigate the relationship between DNA methylation and DNA damage response in photoreceptor cells undergoing cell death in an RP model.
- To explore the therapeutic potential of targeting DNA methyltransferases (DNMTs) in mitigating photoreceptor damage.
Main Methods:
- An RP mouse model was established using methyl methanesulfonate (MMS) injection.
- Retinal structure and function were evaluated using histology (H&E), OCT, TUNEL assay, and electroretinography (ERG).
- The expression of DNA methylation regulators (DNMTs) was assessed by qPCR and Western blot, and the effect of a DNMT inhibitor (5-aza-dC) was evaluated.
Main Results:
- MMS treatment led to significant thinning of the outer nuclear layer (ONL) and photoreceptor cell death, accompanied by hyperexpression of DNMT3A/3B.
- Inhibition of DNMTs using 5-aza-dC suppressed DNMT3A/3B expression, reduced photoreceptor cell damage, and partially restored retinal function.
- The protective effects of 5-aza-dC were correlated with the downregulation of DNMT3A/3B expression.
Conclusions:
- DNMT3A/3B play a functional role in MMS-induced photoreceptor cell damage.
- Targeting DNMTs represents a potential therapeutic strategy for retinal degenerative diseases like RP.
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