MicroRNAs as potential biomarkers for noninvasive detection of fetal trisomy 21

  • Ji Hyae Lim
  • Da Eun Lee
  • Shin Young Kim
  • Hyun Jin Kim
  • Kyeong Sun Kim
  • You Jung Han
  • Min Hyoung Kim
  • Jun Seek Choi
  • Moon Young Kim
  • Hyun Mee Ryu
  • So Yeon Park
Technological Innovations

Abstract

Purpose

The objective of this study was to discover a panel of microRNAs (miRNAs) as potential biomarkers for noninvasive prenatal testing (NIPT) of trisomy 21 (T21) and to predict the biological functions of identified biomarkers using bioinformatics tools.

Methods

Using microarray-based genome-wide expression profiling, we compared the expression levels of miRNAs in whole blood samples from non-pregnant women, whole blood samples from pregnant women with euploid or T21 fetuses, and placenta samples from euploid or T21 fetuses. We analyzed the differentially expressed miRNAs according to disease and tissue type (P value <0.05 and two-fold expression change). To predict functions of target genes of miRNAs, the functional annotation tools were used.

Results

We identified 299 miRNAs which reasonably separate the whole blood from the placenta. Among the identified miRNAs, 150 miRNAs were up-regulated in the placenta, and 149 miRNAs were down-regulated. Most of the up-regulated miRNAs in the placenta were members of the mir-498, mir-379, and mir-127 clusters. Among the up-regulated miRNAs in the placenta, mir-1973 and mir-3196 were expressed at higher levels in the T21 placenta than in the euploid placenta. The two miRNAs potentially regulate 203 target genes that are involved in development of brain, central nervous system, and nervous system. The genes are significantly associated with T21-related disorder such as congenital abnormalities, mental disorders, and nervous system diseases.

Conclusions

Our study indicates placenta-specific miRNAs that may be potential biomarkers for NIPT of fetal T21 and provides new insights into the molecular mechanisms of T21 via regulation of miRNAs.

Keywords

Noninvasive test microRNA Trisomy 21 Placenta 

References

  1. 1.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMedGoogle Scholar
  2. 2.
    Du T, Zamore PD. microPrimer: the biogenesis and function of microRNA. Development. 2005;132:4645–52.CrossRefPubMedGoogle Scholar
  3. 3.
    Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008;9:102–14.CrossRefPubMedGoogle Scholar
  4. 4.
    Szulwach KE, Jin P, Alisch RS. Noncoding RNAs in mental retardation. Clin Genet. 2009;75:209–19.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Huang L, Shen Z, Xu Q, Huang X, Chen Q, Li D. Increased levels of microRNA-424 are associated with the pathogenesis of fetal growth restriction. Placenta. 2013;34:624–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Siew WH, Tan KL, Babaei MA, Cheah PS, Ling KH. MicroRNAs and intellectual disability (ID) in Down syndrome, X-linked ID, and Fragile X syndrome. Front Cell Neurosci. 2013;7:41.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Xu Y, Li W, Liu X, Chen H, Tan K, Chen Y, et al. Identification of dysregulated microRNAs in lymphocytes from children with Down syndrome. Gene. 2013;530:278–86.CrossRefPubMedGoogle Scholar
  8. 8.
    Xu Y, Li W, Liu X, Ma H, Tu Z, Dai Y. Analysis of microRNA expression profile by small RNA sequencing in Down syndrome fetuses. Int J Mol Med. 2013;32:1115–25.PubMedGoogle Scholar
  9. 9.
    Condorelli G, Latronico MV, Cavarretta E. microRNAs in cardiovascular diseases: current knowledge and the road ahead. J Am Coll Cardiol. 2014;63:2177–87.CrossRefPubMedGoogle Scholar
  10. 10.
    Kasinski AL, Adams BD, Slack FJ. Aberrant regulation and function of microRNAs in cancer. Curr Biol. 2014;24:R762–76.CrossRefPubMedGoogle Scholar
  11. 11.
    Chim SS, Shing TK, Hung EC, Leung TY, Lau TK, Chiu RW, et al. Detection and characterization of placental microRNAs in maternal plasma. Clin Chem. 2008;54:482–90.CrossRefPubMedGoogle Scholar
  12. 12.
    Miura K, Miura S, Yamasaki K, Higashijima A, Kinoshita A, Yoshiura K, et al. Identification of pregnancy-associated microRNAs in maternal plasma. Clin Chem. 2010;56:1767–71.CrossRefPubMedGoogle Scholar
  13. 13.
    Kotlabova K, Doucha J, Hromadnikova I. Placental-specific microRNA in maternal circulation – identification of appropriate pregnancy-associated microRNAs with diagnostic potential. J Reprod Immunol. 2011;89:185–91.CrossRefPubMedGoogle Scholar
  14. 14.
    Williams Z, Ben-Dov IZ, Elias R, Mihailovic A, Brown M, Rosenwaks Z, et al. Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations. Proc Natl Acad Sci U S A. 2013;110:4255–60.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Luo SS, Ishibashi O, Ishikawa G, Ishikawa T, Katayama A, Mishima T, et al. Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes. Biol Reprod. 2009;81:717–29.CrossRefPubMedGoogle Scholar
  16. 16.
    Donker RB, Mouillet JF, Chu T, Hubel CA, Stolz DB, Morelli AE, et al. The expression profile of C19MC microRNAs in primary human trophoblast cells and exosomes. Mol Hum Reprod. 2012;18:417–24.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105:10513–8.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Kroh EM, Parkin RK, Mitchell PS, Tewari M. Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). Methods. 2010;50:298–301.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. Williams Obstetrics. 23rd ed. McGraw-Hill’s Medical; 2010. pp. 268.Google Scholar
  20. 20.
    Mégarbané A, Ravel A, Mircher C, Sturtz F, Grattau Y, Rethoré MO, et al. The 50th anniversary of the discovery of trisomy 21: the past, present, and future of research and treatment of Down syndrome. Genet Med. 2009;11:611–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Soifer HS, Rossi JJ, Saetrom P. MicroRNAs in disease and potential therapeutic applications. Mol Ther. 2007;15:2070–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Sethupathy P, Borel C, Gagnebin M, Grant GR, Deutsch S, Elton TS, et al. Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3′ untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. Am J Hum Genet. 2007;81:405–13.CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Elton TS, Sansom SE, Martin MM. Trisomy-21 gene dosage over-expression of miRNAs results in the haploinsufficiency of specific target proteins. RNA Biol. 2010;7:540–7.CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Kotlabova K, Doucha J, Chudoba D, Calda P, Dlouha K, Hromadnikova I. Extracellular chromosome 21-derived microRNAs in euploid & aneuploid pregnancies. Indian J Med Res. 2013;138:935–43.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433:769–73.CrossRefPubMedGoogle Scholar
  26. 26.
    Babak T, Zhang W, Morris Q, Blencowe BJ, Hughes TR. Probing microRNAs with microarrays: tissue specificity and functional inference. RNA. 2004;10:1813–9.CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Morales-Prieto DM, Ospina-Prieto S, Chaiwangyen W, Schoenleben M, Markert UR. Pregnancy-associated miRNA-clusters. J Reprod Immunol. 2013;97:51–61.CrossRefPubMedGoogle Scholar
  28. 28.
    Barch MJ, Knutsen T, Spurbeck JL. The AGT cytogenetics laboratory manual. 3rd ed. New York: Lippincott-Raven; 1997.Google Scholar
  29. 29.
    R Development Core Team, 2006. R: a language and environment for statistical computing. R Foundation for Statistical Computing (http://www.r-project.org. Access April 10, 2013).
  30. 30.
    Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 2006;34:D140–4.CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Maragkakis M, Reczko M, Simossis VA, Alexiou P, Papadopoulos GL, Dalamagas T, et al. DIANA-microT web server: elucidating microRNA functions through target prediction. Nucleic Acids Res. 2009;37:W273–6.CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Betel D, Wilson M, Gabow A, Marks DS, Sander C. The microRNA.org resource: targets and expression. Nucleic Acids Res. 2008;36:D149–53.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Wang X. miRDB: a microRNA target prediction and functional annotation database with a wiki interface. RNA. 2008;14:1012–7.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM, et al. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell. 2006;126:1203–17.CrossRefPubMedGoogle Scholar
  35. 35.
    Bandyopadhyay S, Mitra R. TargetMiner: microRNA target prediction with systematic identification of tissue-specific negative examples. Bioinformatics. 2009;25:2625–31.CrossRefPubMedGoogle Scholar
  36. 36.
    Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel D. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007;27:91–105.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Oliveros JC. 2007. VENNY. An interactive tool for comparing lists with Venn Diagrams. Http://bioinfogp.cnb.csic.es/tools/venny/index.html (Access November 20, 2013).
  38. 38.
    Gilad S, Meiri E, Yogev Y, Benjamin S, Lebanony D, Yerushalmi N, et al. Serum microRNAs are promising novel biomarkers. PLoS One. 2008;3:e3148.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Ji Hyae Lim
    • 1
  • Da Eun Lee
    • 1
  • Shin Young Kim
    • 1
  • Hyun Jin Kim
    • 1
  • Kyeong Sun Kim
    • 1
  • You Jung Han
    • 2
  • Min Hyoung Kim
    • 2
  • Jun Seek Choi
    • 2
  • Moon Young Kim
    • 2
  • Hyun Mee Ryu
    • 1
    • 2
  • So Yeon Park
    • 1
  1. 1.Laboratory of Medical Genetics, Medical Research InstituteCheil General Hospital and Women’s Healthcare CenterSeoulKorea
  2. 2.Department of Obstetrics and Gynecology, Cheil General Hospital and Women’s Healthcare CenterCatholic Kwandong University College of MedicineChung-guSouth Korea

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