The human miRNA repertoire of different blood compounds

BMC Genomics

Andreas Keller¹  Eckart Meese³  Benjamin Meder²  Christina Backes¹  Petra Leidinger³ 

[1] Chair for Clinical Bioinformatics, Saarland University, Saarbrücken, Germany;Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany;Institute of Human Genetics, Saarland University, Homburg, Germany

关键词: Cell separation;    Exosome;    miRNA;   

Others  :  1089816
DOI  :  10.1186/1471-2164-15-474

 received in 2014-04-08, accepted in 2014-06-06,  发布年份 2014

【 摘 要 】

Background

MiRNAs from body fluids gain more and more attraction as biomarker candidates. Besides serum, patterns from whole blood are increasingly considered as markers for human pathologies. Usually, the contribution of different cell types to the respective signature remains however unknown. In this study we provide insights into the human miRNome of different compounds of the blood including CD3, CD14, CD15, CD19, CD56 positive cells as well as exosomes.

Methods

We measured the miRNA repertoire for each cell type and whole blood for two individuals at three time points over the course of one year in order to provide evidence that the cell type miRNomes can be reproducibly detected.

Results

For measurements repeated after 24 hours we found on average correlation of 0.97, even after one year profiles still correlated with 0.96, demonstrating the enormous stability of the cell type specific miRNomes. Highest correlation was found for CD15 positive cells, exceeding Pearson correlation of 0.99. For exosomes a significantly higher variability of miRNA expression was detected. In order to estimate the complexity and variability of the cell type specific miRNomes, we generated profiles for all considered cell types in a total of seven unaffected individuals. While CD15 positive cells showed the most complex miRNome consisting of 328 miRNAs, we detected significantly less miRNAs (186, p = 1.5*10^-5) in CD19 positive cells. Moreover, our analysis showed functional enrichment in many relevant categories such as onco-miRNAs and tumor miRNA suppressors. Interestingly, exosomes were enriched just for onco-miRNAs but not for miRNA tumor suppressors.

Conclusion

In sum, our results provide evidence that blood cell type specific miRNomes are very consistent between individuals and over time.

【 授权许可】

   
2014 Leidinger et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Cheng AM, Byrom MW, Shelton J, Ford LP: Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res 2005, 33(4):1290-1297.
• [2]Pogue AI, Cui JG, Li YY, Zhao Y, Culicchia F, Lukiw WJ: Micro RNA-125b (miRNA-125b) function in astrogliosis and glial cell proliferation. Neurosci Lett 2010, 476(1):18-22.
• [3]Yoshizawa M, Taguchi YH, Yasuda J: Inference of Gene Regulation via miRNAs During ES Cell Differentiation Using MiRaGE Method. Int J Mol Sci 2012, 12(12):9265-9276.
• [4]Yu SL, Chen HY, Chang GC, Chen CY, Chen HW, Singh S, Cheng CL, Yu CJ, Lee YC, Chen HS, Su TJ, Chiang CC, Li HN, Hong QS, Su HY, Chen CC, Chen WJ, Liu CC, Chan WK, Li KC, Chen JJ, Yang PC: MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 2008, 13(1):48-57.
• [5]Ma L, Teruya-Feldstein J, Weinberg RA: Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 2007, 449(7163):682-688.
• [6]Chan JA, Krichevsky AM, Kosik KS: MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005, 65(14):6029-6033.
• [7]Vogel B, Keller A, Frese KS, Leidinger P, Sedaghat-Hamedani F, Kayvanpour E, Kloos W, Backe C, Thanaraj A, Brefort T, Beier M, Hardt S, Meese E, Katus HA, Meder B: Multivariate miRNA signatures as biomarkers for non-ischaemic systolic heart failure. Eur Heart J 2013, 34(36):2812-2823.
• [8]Fu Y, Yi Z, Wu X, Li J, Xu F: Circulating microRNAs in patients with active pulmonary tuberculosis. Journal of clinical microbiology 2011, 49(12):4246-4251.
• [9]Keller A, Leidinger P, Gislefoss R, Haugen A, Langseth H, Staehler P, Lenhof HP, Meese E: Stable serum miRNA profiles as potential tool for non-invasive lung cancer diagnosis. RNA Biol 2011, 8(3):506-516.
• [10]Wang ZX, Bian HB, Wang JR, Cheng ZX, Wang KM, De W: Prognostic significance of serum miRNA-21 expression in human non-small cell lung cancer. J Surg Oncol 2011, 104(7):847-851.
• [11]Gotte M: MicroRNAs in breast cancer pathogenesis. Minerva ginecologica 2010, 62(6):559-571.
• [12]Yin Y, Li M, Li H, Jiang Y, Cao LY, Zhang HF, Xu XC: [Expressions of 6 microRNAs in prostate cancer]. Zhonghua nan ke xue = National journal of andrology 2010, 16(7):599-605.
• [13]Resnick KE, Alder H, Hagan JP, Richardson DL, Croce CM, Cohn DE: The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. Gynecol Oncol 2009, 112(1):55-59.
• [14]Meder B, Keller A, Vogel B, Haas J, Sedaghat-Hamedani F, Kayvanpour E, Just S, Borries A, Rudloff J, Leidinger P, Meese E, Katus HA, Rottbauer W: MicroRNA signatures in total peripheral blood as novel biomarkers for acute myocardial infarction. Basic Res Cardiol 2011, 106(1):13-23.
• [15]Keller A, Leidinger P, Borries A, Wendschlag A, Wucherpfennig F, Scheffler M, Huwer H, Lenhof HP, Meese E: miRNAs in lung cancer - studying complex fingerprints in patient's blood cells by microarray experiments. BMC Cancer 2009, 9:353.
• [16]Keller A, Leidinger P, Lange J, Borries A, Schroers H, Scheffler M, Lenhof HP, Ruprecht K, Meese E: Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls. PLoS One 2009, 4(10):e7440.
• [17]Keller A, Leidinger P, Steinmeyer F, Stahler C, Franke A, Hemmrich-Stanisak G, Kappel A, Wright I, Dorr J, Paul F, Diem R, Tocariu-Krick B, Meder B, Backes C, Meese E, Ruprecht K: Comprehensive analysis of microRNA profiles in multiple sclerosis including next-generation sequencing. Mult Scler 2014, 20(3):295-303.
• [18]Leidinger P, Keller A, Borries A, Reichrath J, Rass K, Jager SU, Lenhof HP, Meese E: High-throughput miRNA profiling of human melanoma blood samples. BMC Cancer 2010, 10:262.
• [19]Hausler SF, Keller A, Chandran PA, Ziegler K, Zipp K, Heuer S, Krockenberger M, Engel JB, Honig A, Scheffler M, Dietl J, Wischhusen J: Whole blood-derived miRNA profiles as potential new tools for ovarian cancer screening. Br J Cancer 2010, 103(5):693-700.
• [20]Leidinger P, Keller A, Borries A, Huwer H, Rohling M, Huebers J, Lenhof HP, Meese E: Specific peripheral miRNA profiles for distinguishing lung cancer from COPD. Lung Cancer 2011, 74(1):41-47.
• [21]Roth P, Wischhusen J, Happold C, Chandran PA, Hofer S, Eisele G, Weller M, Keller A: A specific miRNA signature in the peripheral blood of glioblastoma patients. J Neurochem 2011, 118(3):449-457.
• [22]Leidinger P, Backes C, Deutscher S, Schmitt K, Mueller SC, Frese K, Haas J, Ruprecht K, Paul F, Stahler C, Lang CJ, Meder B, Bartfai T, Meese E, Keller A: A blood based 12-miRNA signature of Alzheimer disease patients. Genome Biol 2013, 14(7):R78.
• [23]Lu M, Shi B, Wang J, Cao Q, Cui Q: TAM: a method for enrichment and depletion analysis of a microRNA category in a list of microRNAs. BMC Bioinformatics 2010, 11:419.
• [24]Beliakova-Bethell N, Massanella M, White C, Lada SM, Du P, Vaida F, Blanco J, Spina CA, Woelk CH: The effect of cell subset isolation method on gene expression in leukocytes. Cytometry A 2014, 85(1):94-104.
• [25]Debey S, Schoenbeck U, Hellmich M, Gathof BS, Pillai R, Zander T, Schultze JL: Comparison of different isolation techniques prior gene expression profiling of blood derived cells: impact on physiological responses, on overall expression and the role of different cell types. Pharmacogenomics J 2004, 4(3):193-207.
• [26]Yu IW, Espinoza DA, McAlexander MA, Witwer KW: OpenArray profiling reveals no differential modulation of miRNA by positive and negative CD4+ T cell immunoselection. Exp Hematol 2014, 42(1):11-13.
• [27]Leidinger P, Keller A, Backes C, Huwer H, Meese E: MicroRNA expression changes after lung cancer resection: A follow-up study. RNA Biol 2012, 9(6):900-910.
• [28]Griffiths-Jones S: miRBase: the microRNA sequence database. Methods Mol Biol 2006, 342:129-138.
• [29]Team R: R: A Language and Environment for Statistical Computing. In. Vienna: R Foundation for Statistical Computing; 2008.