mbtD and celA1 association with ethambutol resistance in Mycobacterium tuberculosis: A multiomics analysis
Ethambutol (EMB) is a first-line antituberculosis drug currently being used clinically to treat tuberculosis. Mutations in the embCAB operon are responsible for EMB resistance. However, the discrepancies between genotypic and phenotypic EMB resistance have attracted much attention. We induced EMB re...
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| Format: | Article |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2022.959911/full |
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| author | Zhuhua Wu Qiuchan Tan Chenchen Zhang Yuchuan Zhao Qinghua Liao Meiling Yu Liuyue Xu Jiawen Wang Hongdi Liang Haicheng Li Liang Chen Xunxun Chen Wenjing Wei |
| author_facet | Zhuhua Wu Qiuchan Tan Chenchen Zhang Yuchuan Zhao Qinghua Liao Meiling Yu Liuyue Xu Jiawen Wang Hongdi Liang Haicheng Li Liang Chen Xunxun Chen Wenjing Wei |
| author_sort | Zhuhua Wu |
| collection | DOAJ |
| description | Ethambutol (EMB) is a first-line antituberculosis drug currently being used clinically to treat tuberculosis. Mutations in the embCAB operon are responsible for EMB resistance. However, the discrepancies between genotypic and phenotypic EMB resistance have attracted much attention. We induced EMB resistance in Mycobacterium tuberculosis in vitro and used an integrated genome–methylome–transcriptome–proteome approach to study the microevolutionary mechanism of EMB resistance. We identified 509 aberrantly methylated genes (313 hypermethylated genes and 196 hypomethylated genes). Moreover, some hypermethylated and hypomethylated genes were identified using RNA-seq profiling. Correlation analysis revealed that the differential methylation of genes was negatively correlated with transcription levels in EMB-resistant strains. Additionally, two hypermethylated candidate genes (mbtD and celA1) were screened by iTRAQ-based quantitative proteomics analysis, verified by qPCR, and corresponded with DNA methylation differences. This is the first report that identifies EMB resistance-related genes in laboratory-induced mono-EMB-resistant M. tuberculosis using multi-omics profiling. Understanding the epigenetic features associated with EMB resistance may provide new insights into the underlying molecular mechanisms. |
| first_indexed | 2024-04-11T11:08:30Z |
| format | Article |
| id | doaj.art-63006530f5bf45dd8b306d6625fb9b13 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-04-11T11:08:30Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-63006530f5bf45dd8b306d6625fb9b132022-12-22T04:28:11ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882022-08-011210.3389/fcimb.2022.959911959911mbtD and celA1 association with ethambutol resistance in Mycobacterium tuberculosis: A multiomics analysisZhuhua Wu0Qiuchan Tan1Chenchen Zhang2Yuchuan Zhao3Qinghua Liao4Meiling Yu5Liuyue Xu6Jiawen Wang7Hongdi Liang8Haicheng Li9Liang Chen10Xunxun Chen11Wenjing Wei12Key Laboratory of Translational Medicine of Guangdong, Center for Tuberculosis Control of Guangdong Province, Guangzhou, ChinaSchool of Basic Medical Sciences, Guangzhou Health Science College, Guangzhou, ChinaKey Laboratory of Translational Medicine of Guangdong, Center for Tuberculosis Control of Guangdong Province, Guangzhou, ChinaKey Laboratory of Translational Medicine of Guangdong, Center for Tuberculosis Control of Guangdong Province, Guangzhou, ChinaKey Laboratory of Translational Medicine of Guangdong, Center for Tuberculosis Control of Guangdong Province, Guangzhou, ChinaKey Laboratory of Translational Medicine of Guangdong, Center for Tuberculosis Control of Guangdong Province, Guangzhou, ChinaKey Laboratory of Translational Medicine of Guangdong, Center for Tuberculosis Control of Guangdong Province, Guangzhou, ChinaKey Laboratory of Translational Medicine of Guangdong, Center for Tuberculosis Control of Guangdong Province, Guangzhou, ChinaKey Laboratory of Translational Medicine of Guangdong, Center for Tuberculosis Control of Guangdong Province, Guangzhou, ChinaThe Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, ChinaKey Laboratory of Translational Medicine of Guangdong, Center for Tuberculosis Control of Guangdong Province, Guangzhou, ChinaKey Laboratory of Translational Medicine of Guangdong, Center for Tuberculosis Control of Guangdong Province, Guangzhou, ChinaKey Laboratory of Translational Medicine of Guangdong, Center for Tuberculosis Control of Guangdong Province, Guangzhou, ChinaEthambutol (EMB) is a first-line antituberculosis drug currently being used clinically to treat tuberculosis. Mutations in the embCAB operon are responsible for EMB resistance. However, the discrepancies between genotypic and phenotypic EMB resistance have attracted much attention. We induced EMB resistance in Mycobacterium tuberculosis in vitro and used an integrated genome–methylome–transcriptome–proteome approach to study the microevolutionary mechanism of EMB resistance. We identified 509 aberrantly methylated genes (313 hypermethylated genes and 196 hypomethylated genes). Moreover, some hypermethylated and hypomethylated genes were identified using RNA-seq profiling. Correlation analysis revealed that the differential methylation of genes was negatively correlated with transcription levels in EMB-resistant strains. Additionally, two hypermethylated candidate genes (mbtD and celA1) were screened by iTRAQ-based quantitative proteomics analysis, verified by qPCR, and corresponded with DNA methylation differences. This is the first report that identifies EMB resistance-related genes in laboratory-induced mono-EMB-resistant M. tuberculosis using multi-omics profiling. Understanding the epigenetic features associated with EMB resistance may provide new insights into the underlying molecular mechanisms.https://www.frontiersin.org/articles/10.3389/fcimb.2022.959911/fullethambutolMycobacterium tuberculosisresistance-related genesdrug resistancemulti-omics |
| spellingShingle | Zhuhua Wu Qiuchan Tan Chenchen Zhang Yuchuan Zhao Qinghua Liao Meiling Yu Liuyue Xu Jiawen Wang Hongdi Liang Haicheng Li Liang Chen Xunxun Chen Wenjing Wei mbtD and celA1 association with ethambutol resistance in Mycobacterium tuberculosis: A multiomics analysis Frontiers in Cellular and Infection Microbiology ethambutol Mycobacterium tuberculosis resistance-related genes drug resistance multi-omics |
| title | mbtD and celA1 association with ethambutol resistance in Mycobacterium tuberculosis: A multiomics analysis |
| title_full | mbtD and celA1 association with ethambutol resistance in Mycobacterium tuberculosis: A multiomics analysis |
| title_fullStr | mbtD and celA1 association with ethambutol resistance in Mycobacterium tuberculosis: A multiomics analysis |
| title_full_unstemmed | mbtD and celA1 association with ethambutol resistance in Mycobacterium tuberculosis: A multiomics analysis |
| title_short | mbtD and celA1 association with ethambutol resistance in Mycobacterium tuberculosis: A multiomics analysis |
| title_sort | mbtd and cela1 association with ethambutol resistance in mycobacterium tuberculosis a multiomics analysis |
| topic | ethambutol Mycobacterium tuberculosis resistance-related genes drug resistance multi-omics |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2022.959911/full |
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