Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4 + T cells of systemic lupus erythematosus
Abstract
DNA hypomethylation plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Here we investigated whether 3-hydroxy butyrate dehydrogenase 2 (BDH2), a modulator of intracellular iron homeostasis, was involved in regulating DNA hypomethylation and hyper-hydroxymethylation in lupus CD4+ T cells. Our results showed that BDH2 expression was decreased, intracellular iron was increased, global DNA hydroxymethylation level was elevated, while methylation level was reduced in lupus CD4+ T cells compared with healthy controls. The decreased BDH2 contributed to DNA hyper-hydroxymethylation and hypomethylation via increasing intracellular iron in CD4+ T cells, which led to overexpression of immune related genes. Moreover, we showed that BDH2 was the target gene of miR-21. miR-21 promoted DNA demethylation in CD4+ T cells through inhibiting BDH2 expression. Our data demonstrated that the dysregulation of iron homeostasis in CD4+ T cells induced by BDH2 deficiency contributes to DNA demethylation and self-reactive T cells in SLE.
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Levels of intracellular iron were increased significantly in SLE CD4+ T cells compared to healthy controls.
“Levels of intracellular iron were increased significantly in SLE CD4+ T cells compared to healthy controls and the researchers suggest a link between iron homeostasis and global DNA methylation status (Zhao et al., 2018), by which SLE T cells exhibit reduced DNA demethylation resulting in enhanced immune-related gene expression.”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Zhao et al., 2018
A link between iron homeostasis and global DNA methylation status has been suggested, by which SLE T cells exhibit reduced DNA demethylation resulting in enhanced immune-related gene expression.
“Levels of intracellular iron were increased significantly in SLE CD4+ T cells compared to healthy controls and the researchers suggest a link between iron homeostasis and global DNA methylation status (Zhao et al., 2018), by which SLE T cells exhibit reduced DNA demethylation resulting in enhanced immune-related gene expression.”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Zhao et al., 2018
Cites
The 1982 revised criteria for the classification of systemic lupus erythematosus
Tan, E. M., Cohen, A. S., Fries, J. F., Masi, A. T., Mcshane, D. J., Rothfield, N. F., Schaller, J. G., Talal, N., & Winchester, R. J. (1982) · Arthritis & Rheumatism · doi:10.1002/art.1780251101 · Cited by 14,519 · see citing works
DNA methylation patterns and epigenetic memory
Bird, A. (2002) · Genes & Development · doi:10.1101/gad.947102 · Cited by 7,124 · see citing works
Tsokos, G. C. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-37754-6.50094-4 · Cited by 3,990 · see citing works
Tsokos, G. C. (2011) · New England Journal of Medicine · doi:10.1056/nejmra1100359 · Cited by 2,747 · see citing works
The International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), Harley, J. B., Alarcón-Riquelme, M. E., Criswell, L. A., Jacob, C. O., Kimberly, R. P., Moser, K. L., Tsao, B. P., Vyse, T. J., & Langefeld, C. D. (2008) · Nature Genetics · doi:10.1038/ng.81 · Cited by 1,309 · see citing works
Epigenetics: Regulation Through Repression
Wolffe, A. P., & Matzke, M. A. (1999) · Science · doi:10.1126/science.286.5439.481 · Cited by 1,241 · see citing works
A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements
Yang, A. S. (2004) · Nucleic Acids Research · doi:10.1093/nar/gnh032 · Cited by 1,033 · see citing works
TETonic shift: biological roles of TET proteins in DNA demethylation and transcription
Pastor, W. A., Aravind, L., & Rao, A. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3589 · Cited by 897 · see citing works
Tumour hypoxia causes DNA hypermethylation by reducing TET activity
Thienpont, B., Steinbacher, J., Zhao, H., D’Anna, F., Kuchnio, A., Ploumakis, A., Ghesquière, B., Van Dyck, L., Boeckx, B., Schoonjans, L., et al. (2016) · Nature · doi:10.1038/nature19081 · Cited by 635 · see citing works
Pan, W. Q., Zhu, S., Yuan, M., Cui, H., Wang, L., Luo, X., Li, J., Zhou, H., Tang, Y., & Shen, N. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0904060 · Cited by 563 · see citing works
Genome-wide Analysis Reveals TET- and TDG-Dependent 5-Methylcytosine Oxidation Dynamics
Shen, L., Wu, H., Diep, D., Yamaguchi, S., D’Alessio, A. C., Fung, H.-L., Zhang, K., & Zhang, Y. (2013) · Cell · doi:10.1016/j.cell.2013.04.002 · Cited by 497 · see citing works
Self-citationPathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective
Moulton, V. R., Suárez‐Fueyo, A., Meidan, E., Li, H., Mizui, M., & Tsokos, G. C. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.05.006 · Cited by 478 · see citing works
Overview of iron metabolism in health and disease
Dev, S., & Babitt, J. L. (2017) · Hemodialysis International · doi:10.1111/hdi.12542 · Cited by 469 · see citing works
Demethylation of CD40LG on the Inactive X in T Cells from Women with Lupus
Lu, Q., Wu, A., Tesmer, L. A., Ray, D., Yousif, N., & Richardson, B. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.9.6352 · Cited by 458 · see citing works
Self-citationCrystal Structure of TET2-DNA Complex: Insight into TET-Mediated 5mC Oxidation
Hu, L., Li, Z., Cheng, J., Rao, Q., Gong, W., Liu, M., Shi, Y. G., Zhu, J., Wang, P., & Xu, Y. (2013) · Cell · doi:10.1016/j.cell.2013.11.020 · Cited by 448 · see citing works
Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis
Mohan, C., & Putterman, C. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.33 · Cited by 376 · see citing works
Zhao, S., Wang, Y., Liang, Y., Zhao, M., Long, H., Ding, S., Yin, H., & Lu, Q. (2010) · Arthritis & Rheumatism · doi:10.1002/art.30196 · Cited by 364 · see citing works
Self-citationDevireddy, L. R., Hart, D. O., Goetz, D. H., & Green, M. R. (2010) · Cell · doi:10.1016/j.cell.2010.04.040 · Cited by 295 · see citing works
Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus
Lu, Q., Kaplan, M. J., Ray, D., Ray, D. W., Zacharek, S. J., Gutsch, D. E., & Richardson, B. (2002) · Arthritis & Rheumatism · doi:10.1002/art.10234 · Cited by 288 · see citing works
Self-citationLu, Q., Wu, A., & Richardson, B. C. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.10.6212 · Cited by 269 · see citing works
Self-citationLei, W., Luo, Y., Lei, W., Luo, Y., Yan, K., Zhao, S., Li, Y., Qiu, X., Zhou, Y., Long, H., et al. (2009) · Scandinavian Journal of Rheumatology · doi:10.1080/03009740902758875 · Cited by 248 · see citing works
Self-citationEnvironmental exposures and the development of systemic lupus erythematosus
Barbhaiya, M., & Costenbader, K. H. (2016) · Current Opinion in Rheumatology · doi:10.1097/bor.0000000000000318 · Cited by 242 · see citing works
Kaplan, M. J., Lu, Q., Wu, A., Attwood, J., & Richardson, B. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.6.3652 · Cited by 225 · see citing works
Self-citationIncreased 5-hydroxymethylcytosine in CD4+ T cells in systemic lupus erythematosus
Zhao, M., Wang, J., Liao, W., Li, D., Li, M., Wu, H., Zhang, Y., Gershwin, M. E., & Lu, Q. (2016) · Journal of Autoimmunity · doi:10.1016/j.jaut.2016.03.001 · Cited by 102 · see citing works
Self-citationInflammation associated anemia and ferritin as disease markers in SLE
Vanarsa, K., Ye, Y., Han, J., Xie, C., Mohan, C., & Wu, T. (2012) · Arthritis Research & Therapy · doi:10.1186/ar4012 · Cited by 101 · see citing works
Hedrich, C. M. (2017) · Current Rheumatology Reports · doi:10.1007/s11926-017-0685-1 · Cited by 97 · see citing works
Zhang, X., He, X., Li, Q., Kong, X., Ou, Z., Zhang, L., Gong, Z., Long, D., Li, J., Zhang, M., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.04.006 · Cited by 76 · see citing works
The key culprit in the pathogenesis of systemic lupus erythematosus: Aberrant DNA methylation
Wu, H., Zhao, M., Tan, L., & Lu, Q. (2016) · Autoimmunity Reviews · doi:10.1016/j.autrev.2016.03.002 · Cited by 75 · see citing works
Self-citationOH, the Places You’ll Go! Hydroxylation, Gene Expression, and Cancer
Ploumakis, A., & Coleman, M. L. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.05.026 · Cited by 74 · see citing works
Regulation of mammalian siderophore 2,5-DHBA in the innate immune response to infection
Liu, Z., Reba, S., Chen, W.-D., Porwal, S. K., Boom, W. H., Petersen, R. B., Rojas, R., Viswanathan, R., & Devireddy, L. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20132629 · Cited by 70 · see citing works
Kim, K.-W., Brown, E. E., Choi, C., Alarcón-Riquelme, M. E., Kelly, J. A., Glenn, S. B., Ojwang, J. O., Adler, A., Lee, H., Boackle, S. A., et al. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2011-201110 · Cited by 68 · see citing works
Early Response of Mouse Joint Tissue to Noninvasive Knee Injury Suggests Treatment Targets
Wu, P., Holguin, N., Silva, M. J., Fu, M., Liao, W., & Sandell, L. J. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38375 · Cited by 59 · see citing works
Tamanaha, E., Guan, S., Marks, K., & Saleh, L. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.6b03243 · Cited by 56 · see citing works
Distinct epigenomes in CD4+ T cells of newborns, middle-ages and centenarians
Zhao, M., Qin, J., Yin, H., et al. (2016) · Scientific Reports · doi:10.1038/srep38411 · Cited by 49 · see citing works
Self-citationLiu, Z., Ciocea, A., & Devireddy, L. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00231-14 · Cited by 41 · see citing works
Epigenetics and Systemic Lupus Erythematosus: Unmet Needs
Meroni, P. L., & Penatti, A. E. (2015) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-015-8497-4 · Cited by 39 · see citing works
Zughaier, S. M., Stauffer, B. B., & McCarty, N. A. (2014) · Journal of Immunology Research · doi:10.1155/2014/140728 · Cited by 34 · see citing works
González‐Cabo, P., Bolinches-Amorós, A., Cabello, J., Ros, S., Moreno, S., Baylis, H. A., Palau, F., & Vázquez‐Manrique, R. P. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.211201 · Cited by 31 · see citing works
Metabolic control of T-cell immunity via epigenetic mechanisms
Zhang, X., Liu, J., & Cao, X. (2017) · Cellular and Molecular Immunology · doi:10.1038/cmi.2017.115 · Cited by 24 · see citing works
3‐Hydroxybutyrate dehydrogenase‐2 and ferritin‐H synergistically regulate intracellular iron
Liu, Z., Velpula, K. K., & Devireddy, L. R. (2014) · FEBS Journal · doi:10.1111/febs.12794 · Cited by 22 · see citing works
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The Role of Iron Regulation in Immunometabolism and Immune-Related Disease
Cronin, S. J. F., Woolf, C. J., Weiss, G., & Penninger, J. M. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00116 · Cited by 299 · see citing works
- Authors
- Zhao, M., Li, M.-Y., Gao, X.-F., Jia, S.-J., Gao, K.-Q., Zhou, Y., Zhang, H.-H., Huang, Y., Wang, J., Wu, H.-J., & Lu, Q.-J.
- Affiliations
- Second Xiangya Hospital of Central South University (CN)
- Corresponding author
- Zhao, Ming
- Venue
- Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 187
- Pages
- 113-121
- ISSN
- 1521-6616 (ISSN-L)
- OpenAlex
- W2765644897
- Cited by
- 66
- References
- 40
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 10 · 2023: 9 · 2022: 17 · 2021: 5 · 2020: 6 · 2019: 4
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81522038, 81220108017, 81430074)
- Hunan Provincial Natural Science Foundation of China (14JJ1009)
- Central South University (2016CX029)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Keywords
- systemic lupus erythematosus, iron homeostasis, DNA demethylation, DNA hydroxymethylation, CD4+ T cells, miR-21, intracellular iron, autoreactive T cells, epigenetic dysregulation
- MeSH terms
- DNA Demethylation, Adult, Animals, Female, Homeostasis, Humans, Hydroxybutyrate Dehydrogenase, Iron, Lupus Erythematosus, Systemic, Male, Mice, Transgenic, Blotting, Western, CD4-Positive T-Lymphocytes, Down-Regulation, Case-Control Studies, Mice, Knockout, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction, MicroRNAs, Epigenesis, Genetic, Mice, Gene Knockdown Techniques, Young Adult, HEK293 Cells
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