Whole genome DNA methylation analysis of active pulmonary tuberculosis disease identifies novel epigenotypes: PARP9/MIR-505/RASGRP4/GNG12 gene methylation and clinical phenotypes

Yung Che Chen*, Chang Chun Hsiao, Ting Wen Chen, Chao Chien Wu, Tung Ying Chao, Sum Yee Leung, Hock Liew Eng, Chiu Ping Lee, Ting Ya Wang, Meng Chih Lin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

We hypothesized that DNA methylation patterns may contribute to the development of active pulmonary tuberculosis (TB). Illumina’s DNA methylation 450 K assay was used to identify differentially methylated loci (DML) in a discovery cohort of 12 active pulmonary TB patients and 6 healthy subjects (HS). DNA methylation levels were validated in an independent cohort of 64 TB patients and 24 HS. Microarray analysis identified 1028 DMLs in TB patients versus HS, and 3747 DMLs in TB patients after versus before anti-TB treatment, while autophagy was the most enriched signaling pathway. In the validation cohort, PARP9 and miR505 genes were hypomethylated in the TB patients versus HS, while RASGRP4 and GNG12 genes were hypermethylated, with the former two further hypomethylated in those with delayed sputum conversion, systemic symptoms, or far advanced lesions. MRPS18B and RPTOR genes were hypomethylated in TB patients with pleural involvement. RASGRP4 gene hypermethylation and RPTOR gene down-regulation were associated with high mycobacterial burden. TB patients with WIPI2/GNG12 hypermethylation or MRPS18B/FOXO3 hypomethylation had lower one-year survival. In vitro ESAT6 and CFP10 stimuli of THP-1 cells resulted in DNA de-methylation changes of the PARP9, RASGRP4, WIPI2, and FOXO3 genes. In conclusions, aberrant DNA methylation over the PARP9/miR505/RASGRP4/GNG12 genes may contribute to the development of active pulmonary TB disease and its clinical phenotypes, while aberrant DNA methylation over the WIPI2/GNG12/MARPS18B/FOXO3 genes may constitute a determinant of long-term outcomes.

Original languageEnglish
Article number3180
JournalInternational journal of molecular sciences
Volume21
Issue number9
DOIs
StatePublished - 1 May 2020

Keywords

  • GNG12
  • MiR505
  • PARP9
  • Pulmonary TB
  • RASGRP4
  • Whole genome DNA methylation

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