Unraveling methylation changes of host macrophages in Mycobacterium tuberculosis infection

Lin Zheng; Eric T Y Leung; H K Wong; Grace Lui; Nelson Lee; Ka-Fai To; K W Choy; Raphael C Y Chan; Margaret Ip

doi:10.1016/j.tube.2016.03.003

Unraveling methylation changes of host macrophages in Mycobacterium tuberculosis infection

Tuberculosis (Edinb). 2016 May:98:139-48. doi: 10.1016/j.tube.2016.03.003. Epub 2016 Mar 21.

Authors

Lin Zheng¹, Eric T Y Leung¹, H K Wong², Grace Lui³, Nelson Lee³, Ka-Fai To⁴, K W Choy², Raphael C Y Chan¹, Margaret Ip⁵

Affiliations

¹ Department of Microbiology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
² Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
³ Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
⁴ Department of Anatomical & Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
⁵ Department of Microbiology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region. Electronic address: margaretip@cuhk.edu.hk.

PMID: 27156630
DOI: 10.1016/j.tube.2016.03.003

Abstract

Objectives: To characterize at high resolution DNA methylation changes of cytokines which occur in the genome of macrophages in association with Mycobacterium tuberculosis (MTB) infection

Methods: We studied the methylation profiles of THP-1 derived macrophage cells infected with clinical MTB strains [Beijing/W & non-Beijing/W lineage, sensitive (INH(S), RIF(S)) & resistant (INH(R), RIF(R)) strains] and of host macrophages from MTB infected cohorts (active & latent patients) with the human methylation CpG islands microarrays.

Results: Methylated modification on the promoter sequences of cytokines and their receptors were found to be associated with MTB infection in a strain- and host-dependent manner. Our epigenetic analyses revealed that infection with Beijing/W MTB strains enhanced IL6R, IL4R and IL17R hyper-methylations in infected macrophages. Validation of IL6R methylated sequence confirmed that MTB infection induced DNA methylation of CpG67 region in the IL6R promoter. In addition, studies on the human macrophage methylation profiles from the patient cohorts indicated that the methylation rate of IL17 family members and related genes were significantly altered in patients with active MTB infections.

Conclusions: Our study offered novel insights into the epigenetic changes in the interaction of host macrophages in MTB infections and warrant further explorations into these changes in modulating the immune response in active and latent MTB infections.

Keywords: Beijing/W strains; IL17; IL6R; Methylation; Mycobacterium tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Case-Control Studies
Cell Line
CpG Islands
Cytokines / genetics*
Cytokines / metabolism
DNA Methylation*
Epigenesis, Genetic*
Host-Pathogen Interactions
Humans
Interleukin-4 Receptor alpha Subunit / genetics
Interleukin-4 Receptor alpha Subunit / metabolism
Latent Tuberculosis / genetics
Latent Tuberculosis / metabolism
Latent Tuberculosis / microbiology
Macrophages / metabolism
Macrophages / microbiology*
Mycobacterium tuberculosis / pathogenicity*
Promoter Regions, Genetic
Receptors, Interleukin / genetics*
Receptors, Interleukin / metabolism
Receptors, Interleukin-17 / genetics
Receptors, Interleukin-17 / metabolism
Receptors, Interleukin-6 / genetics
Receptors, Interleukin-6 / metabolism
Tuberculosis / genetics*
Tuberculosis / metabolism
Tuberculosis / microbiology*

Substances

Cytokines
IL17RA protein, human
IL4R protein, human
IL6R protein, human
Interleukin-4 Receptor alpha Subunit
Receptors, Interleukin
Receptors, Interleukin-17
Receptors, Interleukin-6