Genome-wide DNA methylation and transcriptome changes in Mycobacterium tuberculosis with rifampicin and isoniazid resistance

Liang Chen; Haicheng Li; Tao Chen; Li Yu; Huixin Guo; Yuhui Chen; Mu Chen; Zhenyan Li; Zhuhua Wu; Xuezhi Wang; Jiao Zhao; Huimin Yan; Xinchun Wang; Lin Zhou; Jie Zhou

Genome-wide DNA methylation and transcriptome changes in Mycobacterium tuberculosis with rifampicin and isoniazid resistance

Int J Clin Exp Pathol. 2018 Jun 1;11(6):3036-3045. eCollection 2018.

Authors

Liang Chen¹, Haicheng Li², Tao Chen², Li Yu², Huixin Guo², Yuhui Chen³, Mu Chen⁴, Zhenyan Li², Zhuhua Wu², Xuezhi Wang², Jiao Zhao⁵, Huimin Yan⁶, Xinchun Wang², Lin Zhou¹, Jie Zhou⁷

Affiliations

¹ Centre for Tuberculosis Control of Guangdong Province Guangzhou, China.
² Reference Laboratory, Centre for Tuberculosis Control of Guangdong Province Guangzhou, China.
³ Outpatient Office, Centre for Tuberculosis Control of Guangdong Province Guangzhou, China.
⁴ Department of Respiration, The Sixth Affiliated Hospital of SUN YAT-SEN University Guangzhou 510655, China.
⁵ Medical College of Jinan University Guangzhou, China.
⁶ Guangdong Medical University Dongguan, China.
⁷ The Forth People's Hospital of Foshan Foshan, China.

PMID: 31938429
PMCID: PMC6958063

Abstract

We investigated the genome-wide DNA methylation and transcriptome changes in M. tuberculosis with rifampicin or isoniazid resistance. Single-molecule real-time (SMRT) sequencing and microarray technology were performed to expound DNA methylation profiles and differentially expressed genes in rifampicin or isoniazid resistant M. tuberculosis. Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analysis and methylated regulatory network analysis were conducted by online forecasting databases. Integrated analysis of DNA methylation and transcriptome revealed that 335 differentially methylated genes (175 hypermethylated and 160 hypomethylated) and 132 significant differentially expressed genes (68 up-regulated and 63 down-regulated) were found to be regulated by both rifampicin and isoniazid in M. tuberculosis H37Rv. Correlation analysis showed that differential methylated genes were negatively correlated with their transcriptional levels in rifampicin or isoniazid resistant strains. KEGG pathway analysis indicated that nitrogen metabolism pathway is closely related to differentially methylated genes induced by rifampicin and isoniazid. KEGG also suggested that differentially expressed genes in rifampicin or isoniazid-resistant strains may play different roles in regulating signal transduction events. Furthermore, five differentially methylated candidate genes (Rv0840c, Rv2243, Rv0644c, Rv2386c and Rv1130) in rifampicin resistant strains and three genes (Rv0405, Rv0252 and Rv0908) in isoniazid-resistant strains were verified the existence of protein-protein interaction in STRING database. Integrated DNA methylation and transcriptome analyses provide an epigenetic overview of rifampicin and isoniazid-induced antibiotic resistance in M. tuberculosis H37Rv. Several interesting genes and regulatory pathways may provide valuable resources for epigenetic studies in M. tuberculosis antibiotic resistance.

Keywords: DNA methylation; Epigenetics; Mycobacterium tuberculosis; antibiotic resistance; transcriptome.