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A heterozygous variant in the human cardiac miR-133 gene, MIR133A2, alters miRNA duplex processing and strand abundance

Ohanian, Monique, Humphreys, David T, Anderson, Elizabeth, Preiss, Thomas, Fatkin, Diane·2013·BMC Genetics
DOI 10.1186/1471-2156-14-18PMC PMC3599331
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Abstract

Background: MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Sequential cleavage of miRNA precursors results in a ~22 nucleotide duplex of which one strand, the mature miRNA, is typically loaded into the RNA-induced silencing complex (RISC) while the passenger strand is degraded. Very little is known about how genetic variation might affect miRNA biogenesis and function. Results: We re-sequenced the MIR1-1, MIR1-2, MIR133A1,MIR133A2, and MIR133B genes, that encode the cardiac-enriched miRNAs, miR-1 and miR-133, in 120 individuals with familial atrial fibrillation and identified 10 variants, including a novel 79T > C MIR133A2 substitution. This variant lies within the duplex at the 3′end of the mature strand, miR-133a-3p, and is predicted to prevent base-pairing and weaken thermostability at this site, favoring incorporation of the passenger strand, miR-133a-5p, into RISC. Genomic DNA fragments containing miR-133a-2 precursor sequences with 79T and 79C alleles were transfected into HeLa cells. On Northern blotting the 79T allele showed strong expression of miR-133a-3p with weak expression of miR-133a-5p. In contrast, the 79C allele had no effect on miR-133a-3p but there was a significant increase (mean 3.6-fold) in miR-133a-5p levels. Deep sequencing of small RNA libraries prepared from normal human and murine atria confirmed that nearly all the mature miR-133a was comprised of miR-133a-3p and that levels of miR-133a-5p were very low. A number of isomiRs with variations at 5′and 3′ends were identified for both miR-133a-3p and miR-133a-5p, with 2 predominant miR-133a-3p isomiRs and one predominant miR-133a-5p isomiR. Bioinformatics analyses indicate that the major miR-133a-3p and 5p isomiRs have numerous predicted target mRNAs, only a few of which are in common. Conclusions: Multiple miR-133a isomiRs with potential different mRNA target profiles are present in the atrium in humans and mice. We identified a human 79T > C MIR133A2 variant that alters miRNA processing and results in accumulation of the miR-133a-5p strand that is usually degraded.

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  • A single point mutation (U-C) that affects the relative TS of the human miR-133a duplex results in altered 5p/3p ratios of miR-133a and is associated with atrial fibrillation presumably through effects on mRNA targeting.

    “In another example, a single point mutation (U–C) that affects the relative TS of the human miR‐133a duplex results in altered 5p/3p ratios of miR‐133a and is associated with atrial fibrillation presumably through effects on mRNA targeting (Ohanian et al., 2013; Figure 6d).”

    From microRNA strand selection: Unwinding the rules (2021) · cites this paper as Ohanian et al., 2013

  • miR-21* (3p) downregulation of PPACTR4 appears to decrease protein phosphatase 1 (PP1) activity leading to increased phosphorylation and inactivation of the tumor suppressor Rb/E2F, ultimately resulting in tumorigenesis.

    “miR‐21* (3p) downregulation of PPACTR4 appears to decrease protein phosphatase 1 (PP1) activity leading to increased phosphorylation and inactivation of the tumor suppressor Rb/E2F (retinoblastoma/E2 transcription factor), ultimately resulting in tumorigenesis (Ge et al., 2015; Ohanian et al., 2013).”

    From microRNA strand selection: Unwinding the rules (2021) · cites this paper as Ohanian et al., 2013

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Research works printed but not linked: 32

  1. Fabian MR Sonenberg N Filipowicz W Regulation of mRNA translation and stability by microRNAs Annu Rev Biochem 2010 79 351 379 10.1146/annurev-biochem-060308-103103 20533884 · DOI · Paper page
  2. Kozomara A Griffiths-Jones S miRBase: integrating microRNA annotation and deep-sequencing data Nucleic Acids Res 2011 39 Suppl 1 D152 D157 21037258 PMC3013655
  3. Mendell JT Olson EN MicroRNAs in stress signaling and human disease Cell 2012 148 1172 1187 10.1016/j.cell.2012.02.005 22424228 PMC3308137 · DOI · Paper page
  4. Winter J Jung S Keller S Gregory RI Diederichs S Many roads to maturity: microRNA biogenesis pathways and their regulation Nat Cell Biol 2009 11 228 234 10.1038/ncb0309-228 19255566 · DOI
  5. Fernandez-Valverde SL Taft RJ Mattick JS Dynamic isomiR regulation in Drosophila development RNA 2010 16 1881 1888 10.1261/rna.2379610 20805289 PMC2941097 · DOI · Paper page
  6. Lee LW Zhang S Etheridge A Ma L Martin D Galas D Wang K Complexity of the microRNA repertoire revealed by next-generation sequencing RNA 2010 16 2170 2180 10.1261/rna.2225110 20876832 PMC2957056 · DOI
  7. Humphreys DT Hynes CJ Patel HR Wei GH Cannon L Fatkin D Suter CM Clancy JL Preiss T Complexity of murine cardiomyocyte miRNA biogenesis, sequence variant expression and function PLoS One 2012 7 e30933 10.1371/journal.pone.0030933 22319597 PMC3272019 · DOI
  8. Liang Y Ridzon D Wong L Chen C Characterization of microRNA expression in normal human tissues BMC Genomics 2007 8 166 10.1186/1471-2164-8-166 17565689 PMC1904203 · DOI
  9. Luo X Zhang H Xiao J Wang Z Regulation of human cardiac ion channel genes by microRNAs: theoretical perspective and pathophysiological implications Cell Physiol Biochem 2010 25 571 586 10.1159/000315076 20511702 · DOI
  10. Zhao Y Ransom JF Li A Vedantham V Von Drehle M Muth AN Tsuchihashi T McManus MT Schwartz RJ Srivastava D Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2 Cell 2007 129 303 317 10.1016/j.cell.2007.03.030 17397913 · DOI
  11. Care A Catalucci D Felicetti F Bonci D Addario A Gallo P Bang ML Segnalini P Gu Y Dalton ND Elia L Latronico MV Høydal M Autore C Russo MA Dorn GW II Ellingsen O Ruiz-Lozano P Peterson KL Croce CM Peschle C Condorelli G MicroRNA-133 controls cardiac hypertrophy Nat Med 2007 13 613 618 10.1038/nm1582 17468766 · DOI
  12. Duisters RF Tijsen AJ Schroen B Leenders JJ Lentink V van der Made I Herias V Van Leeuwen RE Schellings MW Barenbrug F Maessen JG Heymans S Pinto YM Creemers EE MiR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling Circ Res 2009 104 170 178 10.1161/CIRCRESAHA.108.182535 19096030 · DOI
  13. Matkovich SJ Wang W Tu Y Eschenbacher WH Dorn LE Condorelli G Diwan A Nerboone JM Dorn GW II MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts Circ Res 2010 106 166 175 10.1161/CIRCRESAHA.109.202176 19893015 PMC2804031 · DOI
  14. Belevych AE Sansom SE Terentyeva R Ho HT Nishijima Y Martin MM Jindal HK Rochira JA Kunitomo Y Abdellatif M Carnes CA Elton TS Györke S Terentyev D MicroRNA-1 and-133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex PLoS One 2011 6 e28324 10.1371/journal.pone.0028324 22163007 PMC3232211 · DOI
  15. Matkovich SJ Van Booven DJ Eschenbacher WH Dorn GW RISC RNA sequencing for context-specific identification of in vivo microRNA targets Circ Res 2011 108 18 26 10.1161/CIRCRESAHA.110.233528 21030712 PMC3017647 · DOI
  16. Girmatsion Z Biliczki P Bonauer A Wimmer-Greinecker G Scherer M Moritz A Bukowska A Goette A Nattel S Hohnloser SH Ehrlich JR Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation Heart Rhythm 2009 6 1802 1809 10.1016/j.hrthm.2009.08.035 19959133 · DOI
  17. Xiao J Liang D Zhang Y Liu Y Zhang H Liu Y Li L Liang X Sun Y Chen YH MicroRNA expression signature in atrial fibrillation with mitral stenosis Physiol Genomics 2011 43 655 664 10.1152/physiolgenomics.00139.2010 21325063 · DOI
  18. Cooley N Cowley MJ Lin RC Marasco S Wong C Kaye DM Dart AM Woodcock EA Influence of atrial fibrillation on microRNA expression profiles in left and right atria from patients with valvular heart disease Physiol Genomics 2012 44 211 219 10.1152/physiolgenomics.00111.2011 22147268 · DOI
  19. De Mena L Coto E Cardo LF Diaz M Blazquez M Ribacoba R Salvador C Pastor P Samaranch L Moris G Menéndez M Corao AI Alvarez V Analysis of the Micro-RNA-133 and PITX3 genes in Parkinson’s disease Am J Med Genet 2010 153B 1234 1239 20468068
  20. Liu N Bezprozvannaya S Williams AH Qi X Richardson JA Bassel-Duby R Olson EN MicroRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart Genes Dev 2008 22 3242 3254 10.1101/gad.1738708 19015276 PMC2600761 · DOI
  21. Saunders MA Liang H Li WH Human polymorphism at microRNAs and microRNA target sites Proc Natl Acad Sci 2007 104 3300 3305 10.1073/pnas.0611347104 17360642 PMC1805605 · DOI
  22. Borel C Antonarakis SE Functional genetic variation of human miRNAs and phenotypic consequences Mamm Genome 2008 19 503 509 10.1007/s00335-008-9137-6 18787897 · DOI
  23. Kim J Bartel DP Allelic imbalance sequencing reveals that single-nucleotide polymorphisms frequently alter microRNA-directed repression Nat Biotechnol 2009 27 472 477 10.1038/nbt.1540 19396161 PMC2828817 · DOI
  24. Ryan BM Robles AI Harris CC Genetic variation in microRNA networks: the implications for cancer research Nat Rev Cancer 2010 10 389 402 10.1038/nrc2867 20495573 PMC2950312 · DOI
  25. Mencia A Modamio-Hoybjor S Redshaw N Morin M Mayo-Merino F Olavarrieta L Aguirre LA Del Castillo I Steel KP Dalmay T Moreno F Moreno-Pelayo MA Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss Nat Genet 2009 41 609 613 10.1038/ng.355 19363479 · DOI · Paper page
  26. Dorn GW II Matkovich SJ Eschenbacher WH Zhang Y A human 3’ miR-499 mutation alters cardiac mRNA targeting and function Circ Res 2012 110 958 967 10.1161/CIRCRESAHA.111.260752 22374132 PMC3320730 · DOI
  27. Yang JS Phillips MD Betel D Mu P Ventura A Siepel AC Chen KC Lai EC Widespread regulatory activity of vertebrate microRNA* species RNA 2011 17 312 326 10.1261/rna.2537911 21177881 PMC3022280 · DOI · Paper page
  28. Starega-Roslan J Krol J Koscianska E Kozlowski P Szlachcic WJ Sobczak K Krzyzosiak WJ Structural basis of miRNA length variety Nucleic Acids Res 2011 39 257 268 10.1093/nar/gkq727 20739353 PMC3017592 · DOI
  29. Marti E Pantano L Banez-Coronel M Llorens F Minones-Moyano E Porta S Sumoy L Ferrer I Estivill X A myriad of miRNA variants in control and Huntington’s disease brain regions detected by massively parallel sequencing Nucleic Acids Res 2010 38 7219 7235 10.1093/nar/gkq575 20591823 PMC2978354 · DOI
  30. Bostjancic E Zidar N Stajer D Glavac D MicroRNAs miR-1, miR-133a, miR-133b, and miR-208 are dysregulated in human myocardial infarction Cardiology 2010 115 163 169 10.1159/000268088 20029200 · DOI
  31. Beilharz TH Humphreys DT Clancy JL Thermann R Martin DI Hentze MW Preiss T MicroRNA-mediated messenger RNA deadenylation contributes to translational repression in mammalian cells PLoS One 2009 4 e6783 10.1371/journal.pone.0006783 19710908 PMC2728509 · DOI
  32. Lewis BP Burge CB Bartel DP Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets Cell 2005 120 15 20 10.1016/j.cell.2004.12.035 15652477 · DOI · Paper page

Cited by

Sorted by citations

Authors
Ohanian, M., Humphreys, D. T., Anderson, E., Preiss, T., & Fatkin, D.
Venue
BMC Genetics
Publisher
Springer Science and Business Media LLC
Published
2013-03-06
Volume
14
Issue
1
ISSN
1471-2156
DOI
10.1186/1471-2156-14-18
PMC
PMC3599331
Cited by
51
References
1
Language
en

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