WTAP Mediated N6-methyladenosine RNA Modification of ELF3 Drives Cellular Senescence by Upregulating IRF8

Zhou, Lei; Zhong, Yun; Wang, Fan; Guo, Yi; Mao, Rui; Xie, Hongfu; Zhang, Yiya; Li, Ji

doi:10.7150/ijbs.90459

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Int J Biol Sci 2024; 20(5):1763-1777. doi:10.7150/ijbs.90459 This issue Cite

Research Paper

WTAP Mediated N6-methyladenosine RNA Modification of ELF3 Drives Cellular Senescence by Upregulating IRF8

Lei Zhou^2,3*, Yun Zhong^1,2*, Fan Wang^1,2, Yi Guo^1,2, Rui Mao^1,2, Hongfu Xie^1,2, Yiya Zhang^1,2,4✉, Ji Li^1,2,4✉

1. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, P.R. China.
2. Hunan key laboratory of aging biology, Xiangya Hospital, Central South University, Changsha, P.R. China.
3. Department of Dermatology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
4. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China, 410008.
* These authors contributed equally to this work.

Citation:

Zhou L, Zhong Y, Wang F, Guo Y, Mao R, Xie H, Zhang Y, Li J. WTAP Mediated N6-methyladenosine RNA Modification of ELF3 Drives Cellular Senescence by Upregulating IRF8. Int J Biol Sci 2024; 20(5):1763-1777. doi:10.7150/ijbs.90459. https://www.ijbs.com/v20p1763.htm

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Abstract

N6-methyladenosine (m6A), the most prevalent posttranscriptional RNA modification, involved in various diseases and cellular processes. However, the underlying mechanisms of m6A regulation in skin aging are still not fully understood. In this study, proteomics analysis revealed a significant correlation between Wilms' tumor 1-associating protein (WTAP) expression and cellular senescence. Next, upregulated WTAP was detected in aging skin tissues and senescent human dermal fibroblasts (HDFs). Functionally, overexpressed WTAP induced senescence and knockdown of WTAP rescued senescence of HDFs. Mechanistically, WTAP directly targeted ELF3 and promoted its expression in an m6A-dependent manner. Exogenous-ELF3 overexpression evidently reversed shWTAP-suppressed fibroblast senescence. Furthermore, ELF3 induced IRF8-mediated senescence-associated secretory phenotype (SASP) by binding to the (-817 to -804) site of the IRF8 promoter directly. In vivo, overexpression of WTAP evidently increased senescence cells in skin and induced skin aging. In summary, these findings revealed the critical role of WTAP-mediated m6A modification in skin aging and identified ELF3 as an important target of m6A modification in HDFs senescence, providing a new idea for delaying the aging process.

Keywords: WTAP, m6A, senescence, ELF3, IRF8

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APA

Zhou, L., Zhong, Y., Wang, F., Guo, Y., Mao, R., Xie, H., Zhang, Y., Li, J. (2024). WTAP Mediated N6-methyladenosine RNA Modification of ELF3 Drives Cellular Senescence by Upregulating IRF8. International Journal of Biological Sciences, 20(5), 1763-1777. https://doi.org/10.7150/ijbs.90459.

ACS

Zhou, L.; Zhong, Y.; Wang, F.; Guo, Y.; Mao, R.; Xie, H.; Zhang, Y.; Li, J. WTAP Mediated N6-methyladenosine RNA Modification of ELF3 Drives Cellular Senescence by Upregulating IRF8. Int. J. Biol. Sci. 2024, 20 (5), 1763-1777. DOI: 10.7150/ijbs.90459.

NLM

CSE

Zhou L, Zhong Y, Wang F, Guo Y, Mao R, Xie H, Zhang Y, Li J. 2024. WTAP Mediated N6-methyladenosine RNA Modification of ELF3 Drives Cellular Senescence by Upregulating IRF8. Int J Biol Sci. 20(5):1763-1777.

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