Increased autophagy activity regulated by LC3B gene promoter DNA methylation is associated with progression to active pulmonary tuberculosis disease
Abstract Background This study aims to explore the role of autophagy-associated genes (ATG) and their epigenetic markers in the progression of mycobacterium tuberculosis (M. tb) infection, and to test the effects of de-methylation agents on macrophage functions against TB. Methods ATG expressions an...
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BMC
2025-03-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-025-03149-1 |
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| author | Yung-Che Chen Ying-Tang Fang Chao-Chien Wu Tung-Ying Chao Yi-Hsi Wang Chia-Cheng Tseng Sum-Yee Leung Chiu-Ping Lee Ting-Ya Wang Po-Yuan Hsu Jen-Chieh Chang Meng-Chih Lin Chang-Chun Hsiao |
| author_facet | Yung-Che Chen Ying-Tang Fang Chao-Chien Wu Tung-Ying Chao Yi-Hsi Wang Chia-Cheng Tseng Sum-Yee Leung Chiu-Ping Lee Ting-Ya Wang Po-Yuan Hsu Jen-Chieh Chang Meng-Chih Lin Chang-Chun Hsiao |
| author_sort | Yung-Che Chen |
| collection | DOAJ |
| description | Abstract Background This study aims to explore the role of autophagy-associated genes (ATG) and their epigenetic markers in the progression of mycobacterium tuberculosis (M. tb) infection, and to test the effects of de-methylation agents on macrophage functions against TB. Methods ATG expressions and their gene promoter DNA methylation levels of blood immune cells were measured in 60 patients with active pulmonary TB disease, 31 subjects with latent TB infection (LTBI), and 15 non-infected healthy subjects (NIHS). An in vitro monocytic THP-1 cell culture model under M. tb-specific antigen stimuli was applied. Results LC3B protein expression of blood M1/M2a monocyte, ATG5 protein expression of M2a, and mean DNA methylation levels of the LC3B gene promoter region of peripheral blood mononuclear cells were all increased in active TB patients versus either LTBI or NIHS group. The LC3B methylation levels were negatively correlated with its protein expressions. The discrimination of active TB disease from LTBI or NIHS was optimally captured by prediction scores, which combined LC3B (+) percentage of blood M1/M2a monocyte, LC3B gene promoter DNA methylation level, male gender, and body mass index. LC3B and ATG5 expressions of both blood M2a and neutrophil were decreased after 6-month anti-TB therapy, but hypermethylated LC3B gene promoter persisted. In vitro 5-Aza-2’-deoxycytidine treatment improved bactericidal, apoptosis and phagocytosis functions through augmenting autophagy flux via mechanisms other than demethylation of the LC3B gene promoter in THP-1 cells. Conclusions Increased LC3B expression and LC3B gene promoter hypermethylation may serve as biomarkers for progression of M. tb infection, while use of de-methylation agent may be a potential approach to host-directed immunotherapy in active TB disease. |
| format | Article |
| id | doaj-art-dc2a2affed264a5cac1587aa59034d17 |
| institution | DOAJ |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
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| series | Respiratory Research |
| spelling | doaj-art-dc2a2affed264a5cac1587aa59034d172025-08-20T03:05:45ZengBMCRespiratory Research1465-993X2025-03-0126111510.1186/s12931-025-03149-1Increased autophagy activity regulated by LC3B gene promoter DNA methylation is associated with progression to active pulmonary tuberculosis diseaseYung-Che Chen0Ying-Tang Fang1Chao-Chien Wu2Tung-Ying Chao3Yi-Hsi Wang4Chia-Cheng Tseng5Sum-Yee Leung6Chiu-Ping Lee7Ting-Ya Wang8Po-Yuan Hsu9Jen-Chieh Chang10Meng-Chih Lin11Chang-Chun Hsiao12Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineGenomics and Proteomics Core Lab, Department of Medical Research, Kaohsiung Chang Gung Memorial HospitalDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineAbstract Background This study aims to explore the role of autophagy-associated genes (ATG) and their epigenetic markers in the progression of mycobacterium tuberculosis (M. tb) infection, and to test the effects of de-methylation agents on macrophage functions against TB. Methods ATG expressions and their gene promoter DNA methylation levels of blood immune cells were measured in 60 patients with active pulmonary TB disease, 31 subjects with latent TB infection (LTBI), and 15 non-infected healthy subjects (NIHS). An in vitro monocytic THP-1 cell culture model under M. tb-specific antigen stimuli was applied. Results LC3B protein expression of blood M1/M2a monocyte, ATG5 protein expression of M2a, and mean DNA methylation levels of the LC3B gene promoter region of peripheral blood mononuclear cells were all increased in active TB patients versus either LTBI or NIHS group. The LC3B methylation levels were negatively correlated with its protein expressions. The discrimination of active TB disease from LTBI or NIHS was optimally captured by prediction scores, which combined LC3B (+) percentage of blood M1/M2a monocyte, LC3B gene promoter DNA methylation level, male gender, and body mass index. LC3B and ATG5 expressions of both blood M2a and neutrophil were decreased after 6-month anti-TB therapy, but hypermethylated LC3B gene promoter persisted. In vitro 5-Aza-2’-deoxycytidine treatment improved bactericidal, apoptosis and phagocytosis functions through augmenting autophagy flux via mechanisms other than demethylation of the LC3B gene promoter in THP-1 cells. Conclusions Increased LC3B expression and LC3B gene promoter hypermethylation may serve as biomarkers for progression of M. tb infection, while use of de-methylation agent may be a potential approach to host-directed immunotherapy in active TB disease.https://doi.org/10.1186/s12931-025-03149-1Pulmonary tuberculosisLatent TB infectionAutophagyLC3BATG5p62 |
| spellingShingle | Yung-Che Chen Ying-Tang Fang Chao-Chien Wu Tung-Ying Chao Yi-Hsi Wang Chia-Cheng Tseng Sum-Yee Leung Chiu-Ping Lee Ting-Ya Wang Po-Yuan Hsu Jen-Chieh Chang Meng-Chih Lin Chang-Chun Hsiao Increased autophagy activity regulated by LC3B gene promoter DNA methylation is associated with progression to active pulmonary tuberculosis disease Respiratory Research Pulmonary tuberculosis Latent TB infection Autophagy LC3B ATG5 p62 |
| title | Increased autophagy activity regulated by LC3B gene promoter DNA methylation is associated with progression to active pulmonary tuberculosis disease |
| title_full | Increased autophagy activity regulated by LC3B gene promoter DNA methylation is associated with progression to active pulmonary tuberculosis disease |
| title_fullStr | Increased autophagy activity regulated by LC3B gene promoter DNA methylation is associated with progression to active pulmonary tuberculosis disease |
| title_full_unstemmed | Increased autophagy activity regulated by LC3B gene promoter DNA methylation is associated with progression to active pulmonary tuberculosis disease |
| title_short | Increased autophagy activity regulated by LC3B gene promoter DNA methylation is associated with progression to active pulmonary tuberculosis disease |
| title_sort | increased autophagy activity regulated by lc3b gene promoter dna methylation is associated with progression to active pulmonary tuberculosis disease |
| topic | Pulmonary tuberculosis Latent TB infection Autophagy LC3B ATG5 p62 |
| url | https://doi.org/10.1186/s12931-025-03149-1 |
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