Genome-wide DNA methylation and transcriptome and proteome changes in Mycobacterium tuberculosis with para-aminosalicylic acid resistance

Previous studies have reported that genome-wide DNA methylation and differentially expressed genes and proteins are closely associated with drug resistance in Mycobacterium tuberculosis (M. tuberculosis). However, no reports have explored such associations in para-aminosalicylic acid (PAS)-resistant M. tuberculosis H37Rv. Here, we investigated genome-wide methylation and transcriptome and proteome changes to explore the associations between specific genes and PAS resistance in M. tuberculosis H37Rv. The results revealed that 1,388 differentially methylated (1,161 hypermethylated and 227 hypomethylated) genes, 214 significantly differentially expressed (103 up- and 111 down-regulated) genes and 137 differentially expressed (48 up- and 89 down-regulated) proteins were regulated by PAS in M. tuberculosis H37Rv. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that metabolic pathways and ABC transporters were closely associated with differentially methylated and expressed genes, respectively. In addition, correlation analysis revealed that differentially methylated genes were negatively correlated with their transcriptional levels in PAS-resistant M. tuberculosis H37Rv. Furthermore, the existence of five hypermethylated candidate genes (esxC, fabG3, fbpB, papA1 and pks2) in PAS-resistant M. tuberculosis H37Rv was verified using protein-protein interaction analysis in the STRING database. The integrated DNA methylation and transcriptome and proteome analysis could provide valuable resources for epigenetics studies in PAS-resistant M. tuberculosis H37Rv.