Abstract
The hallmark of multiple sclerosis (MS) pathogenesis is the breakdown of peripheral tolerance in the immune system. However, its molecular mechanism is not completely understood. Since long non-coding RNAs (lncRNAs) has played important roles in regulation of immunological pathways, here, we evaluated the expression of a novel lncRNA, TOB1-AS1, and its putative associated coding genes in the mechanism of maintaining immune tolerance in peripheral blood of MS patients to assess their possible roles in MS pathogenesis. In this study, 39 MS patients and 32 healthy matched controls were recruited. Real-time PCR standard curve method was used to quantify transcript levels of TOB1-AS1, TOB1, SKP2, and TSG. In addition, the potential sex hormone receptor binding sites on target genes promoter were analyzed using JASPR software. This work demonstrates a negative correlation between TOB1-AS1 expression and EDSS of patients. Also, a robust dysregulation of co-expression of TOB1-AS1 lncRNA and the coding genes in MS patients compared to controls was observed. Such dysregulation in this pathway may be related to MS pathogenesis and response to interferon treatment.
Similar content being viewed by others
References
Arloth, J. (2014). Expression quantitative trait loci as possible biomarkers on depression: Candidate gene and genome-wide approaches.
Atianand, M. K., & Fitzgerald, K. A. (2014). Long non-coding RNAs and control of gene expression in the immune system. Trends in Molecular Medicine,20(11), 623–631.
Baranzini, S. E. (2014). Role of antiproliferative gene Tob1 in the immune system. Clinical and Experimental Neuroimmunology,5(2), 132–136.
Basdeo, S. A., Kelly, S., O’Connell, K., Tubridy, N., McGuigan, C., & Fletcher, J. M. (2016). Increased expression of Tbet in CD4 + T cells from clinically isolated syndrome patients at high risk of conversion to clinically definite MS. SpringerPlus,5(1), 779.
Chen, D., Liu, X., Xia, T., Tekcham, D. S., Wang, W., Chen, H., … Liu, X. (2019). A multidimensional characterization of E3 ubiquitin ligase and substrate interaction network. IScience, 16, 177–191.
Cierny, D., Lehotsky, J., Hanysova, S., Michalik, J., Kantorova, E., Sivak, S., … Jesenska, L. (2017). The age at onset in Multiple Sclerosis is associated with patient’s prognosis. Bratislavske Lekarske Listy, 118(6), 374–377.
Collier, S. P. (2014). TMEVPG1, A Long Noncoding RNA within the Immune System. Vanderbilt University.
Correale, J., Gaitán, M. I., Ysrraelit, M. C., & Fiol, M. P. (2016). Progressive multiple sclerosis: From pathogenic mechanisms to treatment. Brain,140(3), 527–546.
Corvol, J.-C., Pelletier, D., Henry, R. G., Caillier, S. J., Wang, J., Pappas, D., … Oksenberg, J. R. (2008). Abrogation of T cell quiescence characterizes patients at high risk for multiple sclerosis after the initial neurological event. Proceedings of the National Academy of Sciences United States of America, 105(33), 11839–11844.
Dastmalchi, R., Ghafouri-Fard, S., Omrani, M. D., Mazdeh, M., Sayad, A., & Taheri, M. (2018). Dysregulation of long non-coding RNA profile in peripheral blood of multiple sclerosis patients. Multiple Sclerosis and Related Disorders,25, 219–226. https://doi.org/10.1016/j.msard.2018.07.044.
de Andrés, C., Aristimuño, C., de las Heras, V., Martínez-Ginés, M. L., Bartolomé, M., Arroyo, R., … Sánchez-Ramón, S. (2007). Interferon beta-1a therapy enhances CD4 + regulatory T-cell function: An ex vivo and in vitro longitudinal study in relapsing−remitting multiple sclerosis. Journal of Neuroimmunology, 182(1), 204–211.
de Mello, J. B. H., Cirilo, P. D. R., Michelin, O. C., Domingues, M. A. C., Rudge, M. V. C., Rogatto, S. R., et al. (2017). Genomic profile in gestational and non-gestational choriocarcinomas. Placenta,50, 8–15.
Dehghanian, F., Kay, M., & Hojati, Z. (2018). Interferon gamma versus beta-interferon in pathogenesis of multiple sclerosis: Battle of two interferons. In A. Minagar (Ed.), Neuroinflammation (pp. 429–448). Amsterdam: Elsevier.
Dendrou, C. A., Fugger, L., & Friese, M. A. (2015). Immunopathology of multiple sclerosis. Nature Reviews Immunology,15(9), 545–558.
Dolati, S., Marofi, F., Babaloo, Z., Aghebati-Maleki, L., Roshangar, L., Ahmadi, M., … Yousefi, M. (2018). Dysregulated network of mirnas involved in the pathogenesis of multiple sclerosis. Biomedicine & Pharmacotherapy, 104, 280–290.
Driscoll, M. D., Sathya, G., Muyan, M., Klinge, C. M., Hilf, R., & Bambara, R. A. (1998). Sequence requirements for estrogen receptor binding to estrogen response elements. Journal of Biological Chemistry,273(45), 29321–29330.
Ewing, E., Kular, L., Fernandes, S. J., Karathanasis, N., Lagani, V., Ruhrmann, S., … Gomez-Cabrero, D. (2019). Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression. EBioMedicine, 43, 411–423.
Farsani, Z. S., Behmanesh, M., & Sahraian, M. A. (2015). Interleukin-10 but not transforming growth factor-β1 gene expression is up-regulated by vitamin D treatment in multiple sclerosis patients. Journal of the Neurological Sciences,350(1), 18–23.
Gharesouran, J., Taheri, M., Sayad, A., Ghafouri-Fard, S., Mazdeh, M., & Omrani, M. D. (2019). A novel regulatory function of long non-coding RNAs at different levels of gene expression in multiple sclerosis. Journal of Molecular Neuroscience,1, 1–7.
Gonsette, R. E. (2012). Self-tolerance in multiple sclerosis. Acta Neurologica Belgica,112(2), 133–140.
Greer, J. M., & McCombe, P. A. (2011). Role of gender in multiple sclerosis: Clinical effects and potential molecular mechanisms. Journal of Neuroimmunology,234(1), 7–18.
Haines, J., Stewart, G., Compston, A., Ebers, G., Peltonen, L., D’Alfonso, S., … Eraksoy, M. (2003). A meta-analysis of whole genome linkage screens in multiple sclerosis. Journal of Neuroimmunology, 143(1–2), 39–46.
Hiramatsu, Y., Kitagawa, K., Suzuki, T., Uchida, C., Hattori, T., Kikuchi, H., … Yamamoto, T. (2006). Degradation of Tob1 mediated by SCFSkp2-dependent ubiquitination. Cancer Research, 66(17), 8477–8483.
Kornienko, A. E., Dotter, C. P., Guenzl, P. M., Gisslinger, H., Gisslinger, B., Cleary, C., … Barlow, D. P. (2016). Long non-coding RNAs display higher natural expression variation than protein-coding genes in healthy humans. Genome Biology, 17(1), 14.
Korporal, M., Haas, J., Balint, B., Fritzsching, B., Schwarz, A., Moeller, S., … Wildemann, B. (2008). Interferon beta–induced restoration of regulatory T-cell function in multiple sclerosis is prompted by an increase in newly generated naive regulatory T cells. Archives of Neurology, 65(11), 1434–1439.
Maik-Rachline, G., Hacohen-Lev-Ran, A., & Seger, R. (2019). Nuclear ERK: Mechanism of translocation, substrates, and role in cancer. International Journal of Molecular Sciences,20(5), 1194.
Mandrekar, J. N. (2010). Receiver operating characteristic curve in diagnostic test assessment. Journal of Thoracic Oncology,5(9), 1315–1316.
Martins, A. J., Narayanan, M., Prüstel, T., Fixsen, B., Park, K., Gottschalk, R. A., … Wendelsdorf, K. V. (2017). Environment tunes propagation of cell-to-cell variation in the human macrophage gene network. Cell Systems, 4(4), 379–392.
McDonald, W. I., Compston, A., Edan, G., Goodkin, D., Hartung, H., Lublin, F. D., … Reingold, S. C. (2001). Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Annals of Neurology, 50(1), 121–127.
Minagar, A., Ma, W., Zhang, X., Wang, X., Zhang, K., Alexander, J. S., … Albitar, M. (2012). Plasma ubiquitin–proteasome system profile in patients with multiple sclerosis: Correlation with clinical features, neuroimaging, and treatment with interferon-beta-1b. Neurological Research, 34(6), 611–618.
Mowel, W. K., Kotzin, J. J., McCright, S. J., Neal, V. D., & Henao-Mejia, J. (2018). Control of immune cell homeostasis and function by lncRNAs. Trends in Immunology,39(1), 55–69.
Naghavi Gargari, B., Behmanesh, M., & Sahraian, M. A. (2015). Effect of vitamin D treatment on interleukin-2 and interleukin-4 genes expression in multiple sclerosis. Physiology and Pharmacology,19(1), 14–21.
Oskooei, V. K., & Ghafouri-Fard, S. (2019). Are long non-coding RNAs involved in the interaction circuit between estrogen receptor and vitamin D receptor? Meta Gene,19, 1–9.
Preedy, V. R., & Patel, V. B. (2015). Biomarkers in cancer. Berlin: Springer.
Qiu, F., Liang, C.-L., Liu, H., Zeng, Y.-Q., Hou, S., Huang, S., … Dai, Z. (2017). Impacts of cigarette smoking on immune responsiveness: Up and down or upside down? Oncotarget, 8(1), 268.
Ratzer, R., Søndergaard, H. B., Christensen, J. R., Börnsen, L., Borup, R., Sørensen, P. S., et al. (2013). Gene expression analysis of relapsing–remitting, primary progressive and secondary progressive multiple sclerosis. Multiple Sclerosis Journal,19(14), 1841–1848.
Roche, P. J., Hoare, S. A., & Parker, M. G. (1992). A consensus DNA-binding site for the androgen receptor. Molecular Endocrinology,6(12), 2229–2235.
Sakaguchi, S., Powrie, F., & Ransohoff, R. M. (2012). Re-establishing immunological self-tolerance in autoimmune disease. Nature Medicine. https://doi.org/10.1038/nm.2622.
Sandelin, A., Alkema, W., Engström, P., Wasserman, W. W., & Lenhard, B. (2004). JASPAR: An open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Research,32(suppl_1), D91–D94.
Schulze-Topphoff, U., Casazza, S., Varrin-Doyer, M., Pekarek, K., Sobel, R. A., Hauser, S. L., … Baranzini, S. E. (2013). Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity. Journal of Experimental Medicine, 210(7), 1301–1309.
Singh, A. J., Ramsey, S. A., Filtz, T. M., & Kioussi, C. (2018). Differential gene regulatory networks in development and disease. Cellular and Molecular Life Sciences,75(6), 1013–1025.
Spurlock, C. F., III, Tossberg, J. T., Guo, Y., Collier, S. P., Crooke, P. S., III, & Aune, T. M. (2015). Expression and functions of long noncoding RNAs during human T helper cell differentiation. Nature Communications,6, 6932.
Tzachanis, D., & Boussiotis, V. A. (2009). Tob, a member of the APRO family, regulates immunological quiescence and tumor suppression. Cell Cycle,8(7), 1019–1025.
Tzachanis, D., Freeman, G. J., Hirano, N., Van Puijenbroek, A. A. F. L., Delfs, M. W., Berezovskaya, A., … Boussiotis, V. A. (2001). Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nature Immunology, 2(12), 1174–1182.
Tzachanis, D., Lafuente, E. M., Li, L., & Boussiotis, V. A. (2004). Intrinsic and extrinsic regulation of T lymphocyte quiescence. Leukemia & Lymphoma,45(10), 1959–1967.
Tzachanis, D., Li, L., Lafuente, E. M., Berezovskaya, A., Freeman, G. J., & Boussiotis, V. A. (2007). Twisted gastrulation (Tsg) is regulated by Tob and enhances TGF-β signaling in activated T lymphocytes. Blood,109(7), 2944–2952.
Ullah, M. F., Ahmad, A., Bhat, S. H., Abu-Duhier, F. M., Barreto, G. E., & Ashraf, G. M. (2019). Impact of sex differences and gender specificity on behavioral characteristics and pathophysiology of neurodegenerative disorders. Neuroscience & Biobehavioral Reviews,102, 95–105.
Vila, A., Casabella, A. M., Baig, M., Bidot, C. J., & Jones, B. C. (2016). Multiple sclerosis: Enigmatic factors and new controversies. Clinical Case Reports and Reviews. https://doi.org/10.15761/CCRR.1000288.
Wang, D., Qin, H., Du, W., Shen, Y.-W., Lee, W.-H., Riggs, A. D., et al. (2012). Inhibition of S-phase kinase-associated protein 2 (Skp2) reprograms and converts diabetogenic T cells to Foxp3+ regulatory T cells. Proceedings of the National Academy of Sciences USA,109(24), 9493–9498.
Whitacre, C. C., Reingold, S. C., O’looney, P. A., Blankenhorn, E., Brinley, F., Collier, E., … Gilmore, W. (1999). A gender gap in autoimmunity: Task force on gender, multiple sclerosis and autoimmunity. Science, 283(5406), 1277–1278.
Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods (San Diego, Calif.),25(4), 402–408. https://doi.org/10.1006/meth.2001.1262.
Yao, J., Li, Z., Yang, Z., Xue, H., Chang, H., Zhang, X., … Guo, K. (2018). Long noncoding RNA TOB1-AS1, an epigenetically silenced gene, functioned as a novel tumor suppressor by sponging miR-27b in cervical cancer. American Journal of Cancer Research, 8(8), 1483.
Ysrraelit, M. C., & Correale, J. (2019). Impact of sex hormones on immune function and multiple sclerosis development. Immunology,156(1), 9–22.
Zastepa, E., Fitz-Gerald, L., Hallett, M., Antel, J., Bar-Or, A., Baranzini, S., … Haegert, D. G. (2014). Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS. Neurology, 82(8), 681–690.
Acknowledgements
The authors gratefully acknowledge the contribution of the patients and controls for their participation in this study.
Funding
This work is supported by the Iran National Science Foundation and the Department of research Affairs of Tarbiat Modares University.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical Approval
All procedures performed in studies involving human participants were in accordance with the ethics committee of Tarbiat Modares University and with the 1964 Helsinki Declaration.
Informed Consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Dehghanzad, R., Pahlevan Kakhki, M., Alikhah, A. et al. The Putative Association of TOB1-AS1 Long Non-coding RNA with Immune Tolerance: A Study on Multiple Sclerosis Patients. Neuromol Med 22, 100–110 (2020). https://doi.org/10.1007/s12017-019-08567-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-019-08567-1