Genome-Wide DNA Methylation Analysis Reveals Immune Genes in Tuberculosis with Potential Relevance for Host-Directed Interventions.
- 1University Institute of Biochemistry and Biotechnology, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Pakistan.
Abstract
Background
Growing evidence suggests that Mycobacterium tuberculosis (M. tb) infection manipulates the host's epigenetic landscape to evade the immune responses and establish a disease phenotype. Among these epigenetic changes, DNA methylation has emerged as a key mechanism that influences the host immune response, playing a crucial role in either controlling the infection or contributing to disease pathogenesis. M. tb and other pathogens can alter the host's epigenetic landscape to weaken immune defenses and facilitate infection.Objective
In this study we aimed to investigate differential DNA methylation patterns in Tuberculosis (TB) phenotypes i.e., Active, Latent, Cured and healthy controls.Materials and methods
In this study, we investigated genome-wide DNA methylation patterns via Infinium Methylation EPIC array in a total of eight M. tb-exposed patients with two biological replicates in each clinical group: active tuberculosis (TB, n=2), latent TB (n=2), therapy-cleared (cured) TB (n=2) and uninfected controls (n=2). Genes linked to hypermethylated promoters were further analyzed through gene ontology (GO) and biological pathways analyses (DAVID). Motif enrichment analysis was performed using differentially methylated regions (DMRs) (>300bp) and promotor CpG site methylation was correlated with corresponding gene expression profile.Results
Our study identified a repressed immune signature in active TB patients, characterized by hypermethylated genes such as IFNA2, IFNA6, TNFRSF19, IL2, IL21 and TGFβ2 etc. This hypermethylation persists even in cured individuals, despite M. tb clearance and was further reinforced by qPCR analysis showing downregulated expression of hypermethylated genes IFNA2 and IFNA6 in active TB compared to latent and control subjects. Key pathways affected include those associated with tuberculosis, phagosome function, JAK/STAT pathway and cytokine receptors during active M. tb infection, with these effects continuing post-clearance (cured phenotype). Enriched transcription factor motifs within DMRs included ZBTB14, E2F1, and NRF1.Conclusions
Our findings reveal that M. tb infection is marked by a DNA hypermethylation signature linked to key immune-related genes, driving a repressed immune response and active disease manifestation. This epigenetic signature remains even after M. tb is cleared, suggesting long-term alterations in immune regulation. While preliminary, this methylation signatures once validated in larger cohorts highlight the potential for developing early epigenetic markers to help distinguish active TB from other clinical states or to monitor post-treatment immune recovery.
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BibTeX
@article{shahzad2026genomewide,
title = {{Genome-Wide DNA Methylation Analysis Reveals Immune Genes in Tuberculosis with Potential Relevance for Host-Directed Interventions.}},
author = {Hira Shahzad and Mariam Ahmed Mujtaba and Khazina Fatima and Muhammad Ishaq Javed and Pakeeza Arzoo Shaiq and Ghazala Kaukab Raja and Sadia Saeed},
journal = {Iranian journal of biotechnology},
year = {2026},
month = oct,
doi = {10.30498/ijb.2026.546731.4230},
url = {https://europepmc.org/article/MED/42928845},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Genome-Wide DNA Methylation Analysis Reveals Immune Genes in Tuberculosis with Potential Relevance for Host-Directed Interventions.
AU - Hira Shahzad
AU - Mariam Ahmed Mujtaba
AU - Khazina Fatima
AU - Muhammad Ishaq Javed
AU - Pakeeza Arzoo Shaiq
AU - Ghazala Kaukab Raja
AU - Sadia Saeed
PY - 2026
DA - 2026/10/01
JO - Iranian journal of biotechnology
DO - 10.30498/ijb.2026.546731.4230
UR - https://europepmc.org/article/MED/42928845
AB - Background Growing evidence suggests that Mycobacterium tuberculosis (M. tb) infection manipulates the host's epigenetic landscape to evade the immune responses and establish a disease phenotype. Among these epigenetic changes, DNA methylation has emerged as a key mechanism that influences the host immune response, playing a crucial role in either controlling the infection or contributing to disease pathogenesis. M. tb and other pathogens can alter the host's epigenetic landscape to weaken immune defenses and facilitate infection.Objective In this study we aimed to investigate differential DNA methylation patterns in Tuberculosis (TB) phenotypes i.e., Active, Latent, Cured and healthy controls.Materials and methods In this study, we investigated genome-wide DNA methylation patterns via Infinium Methylation EPIC array in a total of eight M. tb-exposed patients with two biological replicates in each clinical group: active tuberculosis (TB, n=2), latent TB (n=2), therapy-cleared (cured) TB (n=2) and uninfected controls (n=2). Genes linked to hypermethylated promoters were further analyzed through gene ontology (GO) and biological pathways analyses (DAVID). Motif enrichment analysis was performed using differentially methylated regions (DMRs) (>300bp) and promotor CpG site methylation was correlated with corresponding gene expression profile.Results Our study identified a repressed immune signature in active TB patients, characterized by hypermethylated genes such as IFNA2, IFNA6, TNFRSF19, IL2, IL21 and TGFβ2 etc. This hypermethylation persists even in cured individuals, despite M. tb clearance and was further reinforced by qPCR analysis showing downregulated expression of hypermethylated genes IFNA2 and IFNA6 in active TB compared to latent and control subjects. Key pathways affected include those associated with tuberculosis, phagosome function, JAK/STAT pathway and cytokine receptors during active M. tb infection, with these effects continuing post-clearance (cured phenotype). Enriched transcription factor motifs within DMRs included ZBTB14, E2F1, and NRF1.Conclusions Our findings reveal that M. tb infection is marked by a DNA hypermethylation signature linked to key immune-related genes, driving a repressed immune response and active disease manifestation. This epigenetic signature remains even after M. tb is cleared, suggesting long-term alterations in immune regulation. While preliminary, this methylation signatures once validated in larger cohorts highlight the potential for developing early epigenetic markers to help distinguish active TB from other clinical states or to monitor post-treatment immune recovery.
SN - 1728-3043
SN - 2322-2921
ER -