MicroRNAs Located in the Hox Gene Clusters Are Implicated in Huntington's Disease Pathogenesis


Transcriptional dysregulation has long been recognized as central to the pathogenesis of Huntington's disease (HD). MicroRNAs (miRNAs) represent a major system of post-transcriptional regulation, by either preventing translational initiation or by targeting transcripts for storage or for degradation. Using next-generation miRNA sequencing in prefrontal cortex (Brodmann Area 9) of twelve HD and nine controls, we identified five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-615-3p and miR-1247-5p) up-regulated in HD at genome-wide significance (FDR q-value<0.05). Three of these, miR-196a-5p, miR-196b-5p and miR-615-3p, were expressed at near zero levels in control brains. Expression was verified for all five miRNAs using reverse transcription quantitative PCR and all but miR-1247-5p were replicated in an independent sample (8HD/8C). Ectopic miR-10b-5p expression in PC12 HTT-Q73 cells increased survival by MTT assay and cell viability staining suggesting increased expression may be a protective response. All of the miRNAs but miR-1247-5p are located in intergenic regions of Hox clusters. Total mRNA sequencing in the same samples identified fifteen of 55 genes within the Hox cluster gene regions as differentially expressed in HD, and the Hox genes immediately adjacent to the four Hox cluster miRNAs as up-regulated. Pathway analysis of mRNA targets of these miRNAs implicated functions for neuronal differentiation, neurite outgrowth, cell death and survival. In regression models among the HD brains, huntingtin CAG repeat size, onset age and age at death were independently found to be inversely related to miR-10b-5p levels. CAG repeat size and onset age were independently inversely related to miR-196a-5p, onset age was inversely related to miR-196b-5p and age at death was inversely related to miR-615-3p expression. These results suggest these Hox-related miRNAs may be involved in neuroprotective response in HD. Recently, miRNAs have shown promise as biomarkers for human diseases and given their relationship to disease expression, these miRNAs are biomarker candidates in HD.


Vyšlo v časopise: MicroRNAs Located in the Hox Gene Clusters Are Implicated in Huntington's Disease Pathogenesis. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004188
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004188

Souhrn

Transcriptional dysregulation has long been recognized as central to the pathogenesis of Huntington's disease (HD). MicroRNAs (miRNAs) represent a major system of post-transcriptional regulation, by either preventing translational initiation or by targeting transcripts for storage or for degradation. Using next-generation miRNA sequencing in prefrontal cortex (Brodmann Area 9) of twelve HD and nine controls, we identified five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-615-3p and miR-1247-5p) up-regulated in HD at genome-wide significance (FDR q-value<0.05). Three of these, miR-196a-5p, miR-196b-5p and miR-615-3p, were expressed at near zero levels in control brains. Expression was verified for all five miRNAs using reverse transcription quantitative PCR and all but miR-1247-5p were replicated in an independent sample (8HD/8C). Ectopic miR-10b-5p expression in PC12 HTT-Q73 cells increased survival by MTT assay and cell viability staining suggesting increased expression may be a protective response. All of the miRNAs but miR-1247-5p are located in intergenic regions of Hox clusters. Total mRNA sequencing in the same samples identified fifteen of 55 genes within the Hox cluster gene regions as differentially expressed in HD, and the Hox genes immediately adjacent to the four Hox cluster miRNAs as up-regulated. Pathway analysis of mRNA targets of these miRNAs implicated functions for neuronal differentiation, neurite outgrowth, cell death and survival. In regression models among the HD brains, huntingtin CAG repeat size, onset age and age at death were independently found to be inversely related to miR-10b-5p levels. CAG repeat size and onset age were independently inversely related to miR-196a-5p, onset age was inversely related to miR-196b-5p and age at death was inversely related to miR-615-3p expression. These results suggest these Hox-related miRNAs may be involved in neuroprotective response in HD. Recently, miRNAs have shown promise as biomarkers for human diseases and given their relationship to disease expression, these miRNAs are biomarker candidates in HD.


Zdroje

1. HDCRG (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72: 971–983.

2. HadziTC, HendricksAE, LatourelleJC, LunettaKL, CupplesLA, et al. (2012) Assessment of cortical and striatal involvement in 523 Huntington disease brains. Neurology 79: 1708–1715.

3. VonsattelJP, MyersRH, StevensTJ, FerranteRJ, BirdED, et al. (1985) Neuropathological classification of Huntington's disease. Journal of neuropathology and experimental neurology 44: 559–577.

4. HodgesA, StrandAD, AragakiAK, KuhnA, SengstagT, et al. (2006) Regional and cellular gene expression changes in human Huntington's disease brain. Human molecular genetics 15: 965–977.

5. ChaJH (2000) Transcriptional dysregulation in Huntington's disease. Trends in neurosciences 23: 387–392.

6. ChaJH (2007) Transcriptional signatures in Huntington's disease. Progress in neurobiology 83: 228–248.

7. LavutA, RavehD (2012) Sequestration of highly expressed mRNAs in cytoplasmic granules, P-bodies, and stress granules enhances cell viability. PLoS genetics 8: e1002527.

8. JunnE, MouradianMM (2012) MicroRNAs in neurodegenerative diseases and their therapeutic potential. Pharmacology & therapeutics 133: 142–150.

9. MartiE, PantanoL, Banez-CoronelM, LlorensF, Minones-MoyanoE, et al. (2010) A myriad of miRNA variants in control and Huntington's disease brain regions detected by massively parallel sequencing. Nucleic acids research 38: 7219–7235.

10. JohnsonR, ZuccatoC, BelyaevND, GuestDJ, CattaneoE, et al. (2008) A microRNA-based gene dysregulation pathway in Huntington's disease. Neurobiology of disease 29: 438–445.

11. PackerAN, XingY, HarperSQ, JonesL, DavidsonBL (2008) The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 28: 14341–14346.

12. SinhaM, GhoseJ, BhattarcharyyaNP (2011) Micro RNA -214,-150,-146a and-125b target Huntingtin gene. RNA biology 8: 1005–1021.

13. ChengPH, LiCL, ChangYF, TsaiSJ, LaiYY, et al. (2013) miR-196a Ameliorates Phenotypes of Huntington Disease in Cell, Transgenic Mouse, and Induced Pluripotent Stem Cell Models. American journal of human genetics 93 (2) 306–12.

14. LeeST, ChuK, ImWS, YoonHJ, ImJY, et al. (2011) Altered microRNA regulation in Huntington's disease models. Experimental neurology 227: 172–179.

15. JinJ, ChengY, ZhangY, WoodW, PengQ, et al. (2012) Interrogation of brain miRNA and mRNA expression profiles reveals a molecular regulatory network that is perturbed by mutant huntingtin. Journal of neurochemistry 123: 477–490.

16. SotrelA, WilliamsRS, KaufmannWE, MyersRH (1993) Evidence for neuronal degeneration and dendritic plasticity in cortical pyramidal neurons of Huntington's disease: a quantitative Golgi study. Neurology 43: 2088–2096.

17. CudkowiczM, KowallNW (1990) Degeneration of pyramidal projection neurons in Huntington's disease cortex. Annals of neurology 27: 200–204.

18. GuX, LiC, WeiW, LoV, GongS, et al. (2005) Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice. Neuron 46: 433–444.

19. RosasHD, HeveloneND, ZaletaAK, GreveDN, SalatDH, et al. (2005) Regional cortical thinning in preclinical Huntington disease and its relationship to cognition. Neurology 65: 745–747.

20. RosasHD, LiuAK, HerschS, GlessnerM, FerranteRJ, et al. (2002) Regional and progressive thinning of the cortical ribbon in Huntington's disease. Neurology 58: 695–701.

21. GreeneLA, TischlerAS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proceedings of the National Academy of Sciences of the United States of America 73: 2424–2428.

22. KitaH, CarmichaelJ, SwartzJ, MuroS, WyttenbachA, et al. (2002) Modulation of polyglutamine-induced cell death by genes identified by expression profiling. Human molecular genetics 11: 2279–2287.

23. WyttenbachA, SwartzJ, KitaH, ThykjaerT, CarmichaelJ, et al. (2001) Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease. Human molecular genetics 10: 1829–1845.

24. IgarashiS, MoritaH, BennettKM, TanakaY, EngelenderS, et al. (2003) Inducible PC12 cell model of Huntington's disease shows toxicity and decreased histone acetylation. Neuroreport 14: 565–568.

25. ApostolBL, IllesK, PallosJ, BodaiL, WuJ, et al. (2006) Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Human molecular genetics 15: 273–285.

26. SugarsKL, BrownR, CookLJ, SwartzJ, RubinszteinDC (2004) Decreased cAMP response element-mediated transcription: an early event in exon 1 and full-length cell models of Huntington's disease that contributes to polyglutamine pathogenesis. The Journal of biological chemistry 279: 4988–4999.

27. LiX, WangCE, HuangS, XuX, LiXJ, et al. (2010) Inhibiting the ubiquitin-proteasome system leads to preferential accumulation of toxic N-terminal mutant huntingtin fragments. Human molecular genetics 19: 2445–2455.

28. AndersS, HuberW (2010) Differential expression analysis for sequence count data. Genome biology 11: R106.

29. BartelDP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136: 215–233.

30. DweepH, StichtC, KharkarA, PandeyP, GretzN (2013) Parallel analysis of mRNA and microRNA microarray profiles to explore functional regulatory patterns in polycystic kidney disease: using PKD/Mhm rat model. PLoS One 8. 8 (1) e53780.

31. SwallaBJ (2006) Building divergent body plans with similar genetic pathways. Heredity (Edinb) 97: 235–243.

32. YektaS, TabinCJ, BartelDP (2008) MicroRNAs in the Hox network: an apparent link to posterior prevalence. Nat Rev Genet 9: 789–796.

33. FlicekP, AhmedI, AmodeMR, BarrellD, BealK, et al. (2013) Ensembl 2013. Nucleic acids research 41: D48–55.

34. RinnJL, KerteszM, WangJK, SquazzoSL, XuX, et al. (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129: 1311–1323.

35. MiyazakiY, AdachiH, KatsunoM, MinamiyamaM, JiangYM, et al. (2012) Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2. Nature medicine 18: 1136–1141.

36. GaughwinPM, CieslaM, LahiriN, TabriziSJ, BrundinP, et al. (2011) Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington's disease. Human molecular genetics 20: 2225–2237.

37. Windemuth AS, I; Pregibon, D; Marini. D. (2012) PubmiR: A Literature Search Tool for MicroRNA Research. Firefly BioWorks, Inc.

38. SinhaM, GhoseJ, DasE, BhattarcharyyaNP (2010) Altered microRNAs in STHdh(Q111)/Hdh(Q111) cells: miR-146a targets TBP. Biochemical and biophysical research communications 396: 742–747.

39. SoldatiC, BithellA, JohnstonC, WongK-Y, StantonLW, et al. (2013) Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of Huntington's disease. J Neurochem 124: 418–430.

40. WolteringJM, DurstonAJ (2008) MiR-10 represses HoxB1a and HoxB3a in zebrafish. PLoS One 3: e1396.

41. TehlerD, Hoyland-KroghsboNM, LundAH (2011) The miR-10 microRNA precursor family. RNA Biol 8: 728–734.

42. FoleyNH, BrayI, WattersKM, DasS, BryanK, et al. (2011) MicroRNAs 10a and 10b are potent inducers of neuroblastoma cell differentiation through targeting of nuclear receptor corepressor 2. Cell death and differentiation 18: 1089–1098.

43. HuangH, XieC, SunX, RitchieRP, ZhangJ, et al. (2010) miR-10a contributes to retinoid acid-induced smooth muscle cell differentiation. J Biol Chem 285: 9383–9389.

44. MeseguerS, MudduluruG, EscamillaJM, AllgayerH, BarettinoD (2011) MicroRNAs-10a and -10b contribute to retinoic acid-induced differentiation of neuroblastoma cells and target the alternative splicing regulatory factor SFRS1 (SF2/ASF). J Biol Chem 286: 4150–4164.

45. PhuaSL, SivakamasundariV, ShaoY, CaiX, ZhangLF, et al. (2011) Nuclear accumulation of an uncapped RNA produced by Drosha cleavage of a transcript encoding miR-10b and HOXD4. PloS one 6: e25689.

46. WeissFU, MarquesIJ, WolteringJM, VleckenDH, AghdassiA, et al. (2009) Retinoic acid receptor antagonists inhibit miR-10a expression and block metastatic behavior of pancreatic cancer. Gastroenterology 137: 2136–2145 e2131–2137.

47. LemonsD, McGinnisW (2006) Genomic evolution of Hox gene clusters. Science 313: 1918–1922.

48. PearsonJC, LemonsD, McGinnisW (2005) Modulating Hox gene functions during animal body patterning. Nature reviews Genetics 6: 893–904.

49. WienholdsE, KloostermanWP, MiskaE, Alvarez-SaavedraE, BerezikovE, et al. (2005) MicroRNA expression in zebrafish embryonic development. Science 309: 310–311.

50. Diez del CorralR, StoreyKG (2004) Opposing FGF and retinoid pathways: a signalling switch that controls differentiation and patterning onset in the extending vertebrate body axis. Bioessays 26: 857–869.

51. SvingenT, TonissenKF (2006) Hox transcription factors and their elusive mammalian gene targets. Heredity (Edinb) 97: 88–96.

52. TaylorHS, AriciA, OliveD, IgarashiP (1998) HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium. J Clin Invest 101: 1379–1384.

53. SchuettengruberB, ChourroutD, VervoortM, LeblancB, CavalliG (2007) Genome regulation by polycomb and trithorax proteins. Cell 128: 735–745.

54. SeongIS, WodaJM, SongJJ, LloretA, AbeyrathnePD, et al. (2010) Huntingtin facilitates polycomb repressive complex 2. Human molecular genetics 19: 573–583.

55. HumbertS (2010) Is Huntington disease a developmental disorder? EMBO reports 11: 899.

56. KirkwoodSC, SiemersE, HodesME, ConneallyPM, ChristianJC, et al. (2000) Subtle changes among presymptomatic carriers of the Huntington's disease gene. Journal of neurology, neurosurgery, and psychiatry 69: 773–779.

57. MyersRH, VonsattelJP, PaskevichPA, KielyDK, StevensTJ, et al. (1991) Decreased neuronal and increased oligodendroglial densities in Huntington's disease caudate nucleus. J Neuropathol Exp Neurol 50: 729–742.

58. LiuJ, Valencia-SanchezMA, HannonGJ, ParkerR (2005) MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nature cell biology 7: 719–723.

59. BalagopalV, ParkerR (2009) Polysomes, P bodies and stress granules: states and fates of eukaryotic mRNAs. Current opinion in cell biology 21: 403–408.

60. BhattacharyyaSN, HabermacherR, MartineU, ClossEI, FilipowiczW (2006) Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125: 1111–1124.

61. CougotN, BhattacharyyaSN, Tapia-ArancibiaL, BordonneR, FilipowiczW, et al. (2008) Dendrites of mammalian neurons contain specialized P-body-like structures that respond to neuronal activation. The Journal of neuroscience : the official journal of the Society for Neuroscience 28: 13793–13804.

62. ZeitelhoferM, KarraD, MacchiP, TolinoM, ThomasS, et al. (2008) Dynamic interaction between P-bodies and transport ribonucleoprotein particles in dendrites of mature hippocampal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 28: 7555–7562.

63. SavasJN, MaB, DeinhardtK, CulverBP, RestituitoS, et al. (2010) A role for huntington disease protein in dendritic RNA granules. The Journal of biological chemistry 285: 13142–13153.

64. SavasJN, MakuskyA, OttosenS, BaillatD, ThenF, et al. (2008) Huntington's disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies. Proceedings of the National Academy of Sciences of the United States of America 105: 10820–10825.

65. SreedharanJ, BlairIP, TripathiVB, HuX, VanceC, et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319: 1668–1672.

66. KwiatkowskiTJJr, BoscoDA, LeclercAL, TamrazianE, VanderburgCR, et al. (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323: 1205–1208.

67. WolozinB (2012) Regulated protein aggregation: stress granules and neurodegeneration. Molecular neurodegeneration 7: 56.

68. GantierMP, McCoyCE, RusinovaI, SaulepD, WangD, et al. (2011) Analysis of microRNA turnover in mammalian cells following Dicer1 ablation. Nucleic acids research 39: 5692–5703.

69. MitchellPS, ParkinRK, KrohEM, FritzBR, WymanSK, et al. (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proceedings of the National Academy of Sciences of the United States of America 105: 10513–10518.

70. ChenX, BaY, MaL, CaiX, YinY, et al. (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell research 18: 997–1006.

71. SchroederA, MuellerO, StockerS, SalowskyR, LeiberM, et al. (2006) The RIN: an RNA integrity number for assigning integrity values to RNA measurements. BMC molecular biology 7: 3.

72. LangmeadB, TrapnellC, PopM, SalzbergSL (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10.

73. QuinlanAR, HallIM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26: 841–842.

74. LivakKJ, SchmittgenTD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402–408.

75. KimD, PerteaG, TrapnellC, PimentelH, KelleyR, et al. (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14 (4) R36.

76. TrapnellC, PachterL, SalzbergSL (2009) TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25: 1105–1111.

77. LiH, HandsakerB, WysokerA, FennellT, RuanJ, et al. (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25: 2078–2079.

78. Durinck SH, W. (2013) biomaRt: Interface to BioMart databases (e.g. Ensembl, COSMIC, Wormbase and Gramene). R. 2.10.0 ed.

79. KasprzykA (2011) BioMart: driving a paradigm change in biological data management. Database (Oxford) 2011

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