Roles of the M6A Methyltransferases METTL3, METTL14, and WTAP in Pulmonary Tuberculosis

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Dec 26

PMID 36569923

Authors

Tian-Ping Zhang

Rui Li

Li-Jun Wang

Qian Huang

Hong-Miao Li

Affiliations

Soon will be listed here.

Abstract

Objective: The aim of the current study was to investigate the contributing role of gene variation and transcription levels among the m6A methyltransferases METTL3, METTL14, and WTAP in pulmonary tuberculosis (PTB).

Methods: A case-control study including 461 PTB patients and 467 normal controls was designed for genotyping. Three SNPs in (rs1061027, rs1139130, rs1061026), three SNPs in (rs62328061, rs4834698, rs1064034), and two SNPs in (rs1853259, rs11752345) were genotyped the SNPscan™ technique. , , and transcription levels were determined in 78 PTB patients and 86 controls quantitative real-time reverse-transcription PCR.

Results: Frequencies of the rs62328061 GG genotype, rs11752345 CT genotype, and T allele were significantly increased in PTB patients compared to controls. An increased risk of rs62328061 was detected in a recessive model, and a decreased risk of rs11752345 was detected in a dominant model in the PTB group. gene variation was not associated with PTB risk. The rs1139130 GG genotype was significantly increased with drug resistance, and the G allele was significantly decreased with drug-induced liver injury in PTB patients. A reduced frequency of the rs62328061 G allele was associated with leukopenia, a reduced frequency of the rs11752345 T allele was associated with sputum smear positivity, and a higher frequency of the rs4834698 TC genotype was evident in PTB patients with hypoproteinemia. Compared to controls, , , and transcription levels in PTB patients were significantly decreased, and the level of WTAP was increased in PTB patients with drug resistance. METTL3 level was negatively associated with erythrocyte sedimentation rate and aspartate aminotransferase, and METTL14 level was negatively correlated with alanine aminotransferase and aspartate aminotransferase.

Conclusion: rs62328061 and rs11752345 variants were associated with the genetic background of PTB, and METTL3, METTL14, and WTAP levels were abnormally decreased, suggesting that these m6A methyltransferases may play important roles in PTB.

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References

Li Z, Zhang Z, He Z, Tang W, Li T, Zeng Z . A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://analysis.bio-x.cn). Cell Res. 2009; 19(4):519-23. DOI: 10.1038/cr.2009.33. View

Caws M, Thwaites G, Dunstan S, Hawn T, Lan N, Thuong N . The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS Pathog. 2008; 4(3):e1000034. PMC: 2268004. DOI: 10.1371/journal.ppat.1000034. View

Liu J, Eckert M, Harada B, Liu S, Lu Z, Yu K . mA mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat Cell Biol. 2018; 20(9):1074-1083. PMC: 6245953. DOI: 10.1038/s41556-018-0174-4. View

Feng Y, Wang F, Pan H, Qiu S, Lu J, Wu L . Obesity-associated gene FTO rs9939609 polymorphism in relation to the risk of tuberculosis. BMC Infect Dis. 2014; 14:592. PMC: 4226896. DOI: 10.1186/s12879-014-0592-2. View

Lin A, Zhou M, Hua R, Zhang J, Zhou H, Li S . METTL3 polymorphisms and Wilms tumor susceptibility in Chinese children: A five-center case-control study. J Gene Med. 2020; 22(11):e3255. DOI: 10.1002/jgm.3255. View

Zhang T, Chen S, Zhang G, Shi S, Wei L, Li H . Association of vitamin D pathway genes polymorphisms with pulmonary tuberculosis susceptibility in a Chinese population. Genes Nutr. 2021; 16(1):6. PMC: 8061222. DOI: 10.1186/s12263-021-00687-3. View

Deng X, Su R, Weng H, Huang H, Li Z, Chen J . RNA N-methyladenosine modification in cancers: current status and perspectives. Cell Res. 2018; 28(5):507-517. PMC: 5951805. DOI: 10.1038/s41422-018-0034-6. View

Shell S, Prestwich E, Baek S, Shah R, Sassetti C, Dedon P . DNA methylation impacts gene expression and ensures hypoxic survival of Mycobacterium tuberculosis. PLoS Pathog. 2013; 9(7):e1003419. PMC: 3701705. DOI: 10.1371/journal.ppat.1003419. View

Ping X, Sun B, Wang L, Xiao W, Yang X, Wang W . Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014; 24(2):177-89. PMC: 3915904. DOI: 10.1038/cr.2014.3. View

10.

Ortega E, Hernandez-Bazan S, Sanchez-Hernandez B, Licona-Limon I, Fuentes-Dominguez J . Single Nucleotide Polymorphisms in Affect Susceptibility to Tuberculosis in Mexican Population from the State of Veracruz. J Immunol Res. 2020; 2020:2965697. PMC: 7204096. DOI: 10.1155/2020/2965697. View

11.

Ji G, Zhang M, Liu Q, Wu S, Wang Y, Chen G . Functional Polymorphism in the Gene Associated With Tuberculosis Susceptibility. Front Immunol. 2021; 12:660384. PMC: 8181729. DOI: 10.3389/fimmu.2021.660384. View

12.

Luo A, Yang L, Li M, Cai M, Huang A, Liu X . Genetic Variants in are Associated with the Risk of Acute Lymphoblastic Leukemia in Southern Chinese Children: A Five-Center Case-Control Study. Cancer Manag Res. 2021; 13:9189-9200. PMC: 8684373. DOI: 10.2147/CMAR.S335925. View

13.

He L, Li H, Wu A, Peng Y, Shu G, Yin G . Functions of N6-methyladenosine and its role in cancer. Mol Cancer. 2019; 18(1):176. PMC: 6892141. DOI: 10.1186/s12943-019-1109-9. View

14.

Chen X, Xu M, Xu X, Zeng K, Liu X, Sun L . RETRACTED: METTL14 Suppresses CRC Progression via Regulating N6-Methyladenosine-Dependent Primary miR-375 Processing. Mol Ther. 2019; 28(2):599-612. PMC: 7001002. DOI: 10.1016/j.ymthe.2019.11.016. View

15.

Orouji E, Peitsch W, Orouji A, Houben R, Utikal J . Oncogenic Role of an Epigenetic Reader of mA RNA Modification: YTHDF1 in Merkel Cell Carcinoma. Cancers (Basel). 2020; 12(1). PMC: 7016651. DOI: 10.3390/cancers12010202. View

16.

Zhuo Z, Hua R, Zhang H, Lin H, Fu W, Zhu J . METTL14 gene polymorphisms decrease Wilms tumor susceptibility in Chinese children. BMC Cancer. 2021; 21(1):1294. PMC: 8643011. DOI: 10.1186/s12885-021-09019-5. View

17.

Gagneux S . Host-pathogen coevolution in human tuberculosis. Philos Trans R Soc Lond B Biol Sci. 2012; 367(1590):850-9. PMC: 3267123. DOI: 10.1098/rstb.2011.0316. View

18.

Gong Z, Wang G, Zeng J, Stojkoska A, Huang H, Xie J . Differential DNA methylomes of clinical MDR, XDR and XXDR isolates revealed by using single-molecule real-time sequencing. J Drug Target. 2020; 29(1):69-77. DOI: 10.1080/1061186X.2020.1797049. View

19.

Schmittgen T, Livak K . Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008; 3(6):1101-8. DOI: 10.1038/nprot.2008.73. View

20.

Wang M, Kong W, He B, Li Z, Song H, Shi P . Vitamin D and the promoter methylation of its metabolic pathway genes in association with the risk and prognosis of tuberculosis. Clin Epigenetics. 2018; 10(1):118. PMC: 6136159. DOI: 10.1186/s13148-018-0552-6. View