DNA methylation regulates the extinction of fear memory

doi:10.5498/wjp.v15.i7.107524

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Jul 19, 2025 (publication date) through Feb 13, 2026

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World Journal of Psychiatry

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World J Psychiatry. Jul 19, 2025; 15(7): 107524
Published online Jul 19, 2025. doi: 10.5498/wjp.v15.i7.107524

DNA methylation regulates the extinction of fear memory

Le Jiang, Rui-Xue Ma, Er-Shu He, Xiao-Ye Zheng, Xin Peng, Wen-Hao Ma, Ying Li, Han-Wei li, Xue-Yan Zhang, Jie-Yu Ji, Yan-Jiao Li, Shang-Lan Qu, Li-Juan Li, Zhi-Ting Gong

Le Jiang, Rui-Xue Ma, Er-Shu He, Xiao-Ye Zheng, Xin Peng, Wen-Hao Ma, Ying Li, Han-Wei li, Xue-Yan Zhang, Jie-Yu Ji, Yan-Jiao Li, Shang-Lan Qu, Li-Juan Li, Zhi-Ting Gong, School of Medicine, Dali University, Dali 671003, Yunnan Province, China

Le Jiang, School of Medicine, Xinjiang College of Science and Technology, Korla 841000, Xinjiang Uighur Autonomous Region, China

Shang-Lan Qu, Faculty of Health and Medical Sciences, Taylor’s University, Subang Jaya 47500, Selangor, Malaysia

Co-first authors: Le Jiang and Rui-Xue Ma.

Co-corresponding authors: Li-Juan Li and Zhi-Ting Gong.

Author contributions: Gong ZT, Li LJ contributed to conceptualization;, Jiang L, Ma RX, Gong ZT, and Li LJ contributed to data curation; Jiang L, Ma RX, Gong ZT, and Li LJ contributed to formal analysis; Li YJ, Li LJ, and Gong ZT contributed to funding acquisition; Jiang L, Ma RX, He ES, Li LJ, and Gong ZT contributed to methodology; Jiang L, Ma RX, and Gong ZT contributed to project administration; Li LJ and Gong ZT contributed to supervision; Jiang L, Ma RX, He ES, Zheng XY, Peng X, Ma WH, Li Y, Li HW, Zhang XY, Ji JY, Li YJ, Qu SL, and Gong ZT contributed to validation; Jiang L, Ma RX, Gong ZT, and Li LJ contributed to writing–original draft; Jiang L, Ma RX, He ES, Zheng XY, Peng X, Ma WH, Li Y, Li HW, Zhang XY, Ji JY, Li YJ, Qu SL, Li LJ, and Gong ZT contributed to writing – review and editing.

Supported by National Natural Science Foundation of China, No. 82360231; Yunnan Basic Research Program General Project, No. 202401AT070075; Dali Basic Research Program Key Project, No. 202301A020021; and Youth Special Project for Basic Research of Local Universities in Yunnan Province, No. 202301BA070001-127.

Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Dali University (Protocol No. 2022-P2-119).

Conflict-of-interest statement: The authors declare no conflicts of interest.

ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.

Data sharing statement: Data can be found in https://data.mendeley.com/datasets/sb4pr258f2/1.

Corresponding author: Zhi-Ting Gong, Associate Professor, School of Medicine, Dali University, No. 2 Hongsheng Road, Dali 671003, Yunnan Province, China. gzhting@foxmail.com

Received: March 30, 2025
Revised: April 23, 2025
Accepted: May 19, 2025
Published online: July 19, 2025
Processing time: 102 Days and 2.8 Hours

Abstract

BACKGROUND

Fear-related disorders, such as post-traumatic stress disorder (PTSD), significantly impact patients and families. Exposure therapy is a common treatment, but improving its effectiveness remains a key challenge. Fear conditioning and extinction in animal models offer insights into its mechanisms. Our previous research indicates that DNA methyltransferases play a role in fear memory renewal.

AIM

To investigate the role of DNA methylation in the extinction of fear memory, with the goal of identifying potential strategies to enhance the efficacy of exposure therapy for fear-related disorders.

METHODS

This study investigated the role of DNA methylation in fear memory extinction in mice. DNA methylation was manipulated using N-phthalyl-L-tryptophan (RG108) to reduce methylation and L-methionine injections to enhance it. Neuronal activity, and dendritic spine density was measured following extinction training.

RESULTS

RG108 suppressed extinction, reduced spine density, and inhibited neuronal activity. Methionine injections facilitated extinction.

CONCLUSION

DNA methylation is crucial for fear memory extinction. Enhancing methylation may improve the efficacy of exposure therapy, offering a potential strategy to treat fear-related disorders.

Keywords: RG108; DNA methylation; Fear memory; Exposure therapy; Extinction

Core Tip: Reduced methylation by RG108 suppresses extinction, reduces spine density, and inhibits neuronal activity; enhancing methylation by L-methionine improves the efficacy of exposure therapy, offering a potential strategy to treat fear-related disorders.