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

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2024 Mar 14

PMID 38481803

Authors

Lei Zhou

Yun Zhong

Fan Wang

Yi Guo

Rui Mao

Hongfu Xie

Yiya Zhang

Ji Li

Affiliations

Soon will be listed here.

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. , 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.

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References

Chen X, Gong W, Shao X, Shi T, Zhang L, Dong J . METTL3-mediated mA modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression. Ann Rheum Dis. 2021; 81(1):87-99. DOI: 10.1136/annrheumdis-2021-221091. View

Xian J, Shang M, Dai Y, Wang Q, Long X, Li J . N-methyladenosine-modified long non-coding RNA AGAP2-AS1 promotes psoriasis pathogenesis via miR-424-5p/AKT3 axis. J Dermatol Sci. 2021; 105(1):27-36. DOI: 10.1016/j.jdermsci.2021.11.007. View

Yang Z, Yang S, Cui Y, Wei J, Shah P, Park G . METTL14 facilitates global genome repair and suppresses skin tumorigenesis. Proc Natl Acad Sci U S A. 2021; 118(35). PMC: 8536359. DOI: 10.1073/pnas.2025948118. View

Zhang X, Pearsall V, Carver C, Atkinson E, Clarkson B, Grund E . Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance. Nat Commun. 2022; 13(1):5671. PMC: 9515187. DOI: 10.1038/s41467-022-33226-8. View

Sasaki N, Itakura Y, Toyoda M . Rapamycin promotes endothelial-mesenchymal transition during stress-induced premature senescence through the activation of autophagy. Cell Commun Signal. 2020; 18(1):43. PMC: 7069020. DOI: 10.1186/s12964-020-00533-w. View

Waaijer M, Goldeck D, Gunn D, van Heemst D, Westendorp R, Pawelec G . Are skin senescence and immunosenescence linked within individuals?. Aging Cell. 2019; 18(4):e12956. PMC: 6612632. DOI: 10.1111/acel.12956. View

Low E, Alimohammadiha G, Smith L, Costello L, Przyborski S, von Zglinicki T . How good is the evidence that cellular senescence causes skin ageing?. Ageing Res Rev. 2021; 71:101456. PMC: 8524668. DOI: 10.1016/j.arr.2021.101456. View

Childs B, Gluscevic M, Baker D, Laberge R, Marquess D, Dananberg J . Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov. 2017; 16(10):718-735. PMC: 5942225. DOI: 10.1038/nrd.2017.116. View

Zhao B, Roundtree I, He C . Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2016; 18(1):31-42. PMC: 5167638. DOI: 10.1038/nrm.2016.132. View

10.

Choi E . Aging of the skin barrier. Clin Dermatol. 2019; 37(4):336-345. DOI: 10.1016/j.clindermatol.2019.04.009. View

11.

Ouyang M, Fang J, Wang M, Huang X, Lan J, Qu Y . Advanced glycation end products alter the mA-modified RNA profiles in human dermal fibroblasts. Epigenomics. 2022; 14(8):431-449. DOI: 10.2217/epi-2022-0016. View

12.

Li F, Zhao D, Wu J, Shi Y . Structure of the YTH domain of human YTHDF2 in complex with an m(6)A mononucleotide reveals an aromatic cage for m(6)A recognition. Cell Res. 2014; 24(12):1490-2. PMC: 4260351. DOI: 10.1038/cr.2014.153. View

13.

Huang H, Weng H, Sun W, Qin X, Shi H, Wu H . Recognition of RNA N-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018; 20(3):285-295. PMC: 5826585. DOI: 10.1038/s41556-018-0045-z. View

14.

Luo W, Tong Z, Cao P, Wang F, Liu Y, Zheng Z . Transcription-independent regulation of STING activation and innate immune responses by IRF8 in monocytes. Nat Commun. 2022; 13(1):4822. PMC: 9381507. DOI: 10.1038/s41467-022-32401-1. View

15.

Xie H, Zhou L, Liu F, Long J, Yan S, Xie Y . Autophagy induction regulates aquaporin 3-mediated skin fibroblast ageing. Br J Dermatol. 2021; 186(2):318-333. DOI: 10.1111/bjd.20662. View

16.

Baker D, Wijshake T, Tchkonia T, LeBrasseur N, Childs B, van de Sluis B . Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011; 479(7372):232-6. PMC: 3468323. DOI: 10.1038/nature10600. View

17.

Hernandez-Segura A, Nehme J, Demaria M . Hallmarks of Cellular Senescence. Trends Cell Biol. 2018; 28(6):436-453. DOI: 10.1016/j.tcb.2018.02.001. View

18.

Jiang Z, Wang Y, Li Z, Dai Z, He Y, Chu K . The m6A mRNA demethylase FTO in granulosa cells retards FOS-dependent ovarian aging. Cell Death Dis. 2021; 12(8):744. PMC: 8316443. DOI: 10.1038/s41419-021-04016-9. View

19.

Yang B, Dan X, Hou Y, Lee J, Wechter N, Krishnamurthy S . NAD supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy. Aging Cell. 2021; 20(4):e13329. PMC: 8045911. DOI: 10.1111/acel.13329. View

20.

Zhang B, Wu Q, Li B, Wang D, Wang L, Zhou Y . mA regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer. Mol Cancer. 2020; 19(1):53. PMC: 7066851. DOI: 10.1186/s12943-020-01170-0. View