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Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington’s Disease and Other Neurodegenerative Disorders

Molecular Neurobiology volume 54, pages 3859–3878 (2017)Cite this article

Abstract

Retinoic acid (RA) signaling through retinoic acid receptors (RARs), known for its multiple developmental functions, emerged more recently as an important regulator of adult brain physiology. How RAR-mediated regulation is achieved is poorly known, partly due to the paucity of information on critical target genes in the brain. Also, it is not clear how reduced RA signaling may contribute to pathophysiology of diverse neuropsychiatric disorders. We report the first genome-wide analysis of RAR transcriptional targets in the brain. Using chromatin immunoprecipitation followed by high-throughput sequencing and transcriptomic analysis of RARβ-null mutant mice, we identified genomic targets of RARβ in the striatum. Characterization of RARβ transcriptional targets in the mouse striatum points to mechanisms through which RAR may control brain functions and display neuroprotective activity. Namely, our data indicate with statistical significance (FDR 0.1) a strong contribution of RARβ in controlling neurotransmission, energy metabolism, and transcription, with a particular involvement of G-protein coupled receptor (p = 5.0e−5), cAMP (p = 4.5e−4), and calcium signaling (p = 3.4e−3). Many identified RARβ target genes related to these pathways have been implicated in Alzheimer’s, Parkinson’s, and Huntington’s disease (HD), raising the possibility that compromised RA signaling in the striatum may be a mechanistic link explaining the similar affective and cognitive symptoms in these diseases. The RARβ transcriptional targets were particularly enriched for transcripts affected in HD. Using the R6/2 transgenic mouse model of HD, we show that partial sequestration of RARβ in huntingtin protein aggregates may account for reduced RA signaling reported in HD.

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References

  1. Kane MA, Chen N, Sparks S, Napoli JL (2005) Quantification of endogenous retinoic acid in limited biological samples by LC/MS/MS. Biochem J 388(Pt 1):363–369

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Krezel W, Kastner P, Chambon P (1999) Differential expression of retinoid receptors in the adult mouse central nervous system. Neuroscience 89(4):1291–1300

    CAS  Article  PubMed  Google Scholar 

  3. Zetterstrom RH, Simon A, Giacobini MM, Eriksson U, Olson L (1994) Localization of cellular retinoid-binding proteins suggests specific roles for retinoids in the adult central nervous system. Neuroscience 62(3):899–918

    CAS  Article  PubMed  Google Scholar 

  4. Krezel W, Ghyselinck N, Samad TA, Dupe V, Kastner P, Borrelli E, Chambon P (1998) Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279(5352):863–867

    CAS  Article  PubMed  Google Scholar 

  5. Krzyzosiak A, Szyszka-Niagolov M, Wietrzych M, Gobaille S, Muramatsu S, Krezel W (2010) Retinoid x receptor gamma control of affective behaviors involves dopaminergic signaling in mice. Neuron 66(6):908–920

    CAS  Article  PubMed  Google Scholar 

  6. Liao WL, Tsai HC, Wang HF, Chang J, Lu KM, Wu HL, Lee YC, Tsai TF et al (2008) Modular patterning of structure and function of the striatum by retinoid receptor signaling. Proc Natl Acad Sci U S A 105(18):6765–6770

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Rataj-Baniowska M, Niewiadomska-Cimicka A, Paschaki M, Szyszka-Niagolov M, Carramolino L, Torres M, Dolle P, Krezel W (2015) Retinoic acid receptor beta controls development of striatonigral projection neurons through FGF-dependent and Meis1-dependent mechanisms. J Neurosci 35(43):14467–14475

    CAS  Article  PubMed  Google Scholar 

  8. Wietrzych-Schindler M, Szyszka-Niagolov M, Ohta K, Endo Y, Perez E, de Lera AR, Chambon P, Krezel W (2011) Retinoid x receptor gamma is implicated in docosahexaenoic acid modulation of despair behaviors and working memory in mice. Biol Psychiatry 69(8):788–794

    CAS  Article  PubMed  Google Scholar 

  9. Lane MA, Bailey SJ (2005) Role of retinoid signalling in the adult brain. Prog Neurobiol 75(4):275–293

    CAS  Article  PubMed  Google Scholar 

  10. Balmer JE, Blomhoff R (2002) Gene expression regulation by retinoic acid. J Lipid Res 43(11):1773–1808

    CAS  Article  PubMed  Google Scholar 

  11. de The H, Vivanco-Ruiz MM, Tiollais P, Stunnenberg H, Dejean A (1990) Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature 343(6254):177–180

    Article  PubMed  Google Scholar 

  12. Sucov HM, Murakami KK, Evans RM (1990) Characterization of an autoregulated response element in the mouse retinoic acid receptor type beta gene. Proc Natl Acad Sci U S A 87(14):5392–5396

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Samad TA, Krezel W, Chambon P, Borrelli E (1997) Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family. Proc Natl Acad Sci U S A 94(26):14349–14354

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Crittenden JR, Graybiel AM (2011) Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments. Front Neuroanat 5:59

    Article  PubMed  PubMed Central  Google Scholar 

  15. Galter D, Buervenich S, Carmine A, Anvret M, Olson L (2003) ALDH1 mRNA: presence in human dopamine neurons and decreases in substantia nigra in Parkinson’s disease and in the ventral tegmental area in schizophrenia. Neurobiol Dis 14(3):637–647

    CAS  Article  PubMed  Google Scholar 

  16. Corcoran JP, So PL, Maden M (2004) Disruption of the retinoid signalling pathway causes a deposition of amyloid beta in the adult rat brain. Eur J Neurosci 20(4):896–902

    Article  PubMed  Google Scholar 

  17. Rinaldi P, Polidori MC, Metastasio A, Mariani E, Mattioli P, Cherubini A, Catani M, Cecchetti R et al (2003) Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiol Aging 24(7):915–919

    CAS  Article  PubMed  Google Scholar 

  18. Goncalves MB, Clarke E, Hobbs C, Malmqvist T, Deacon R, Jack J, Corcoran JP (2013) Amyloid beta inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor alpha agonist. Eur J Neurosci 37(7):1182–1192

    Article  PubMed  PubMed Central  Google Scholar 

  19. Fitzmaurice AG, Rhodes SL, Lulla A, Murphy NP, Lam HA, O’Donnell KC, Barnhill L, Casida JE et al (2013) Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. Proc Natl Acad Sci U S A 110(2):636–641

    CAS  Article  PubMed  Google Scholar 

  20. Hodges A, Strand AD, Aragaki AK, Kuhn A, Sengstag T, Hughes G, Elliston LA, Hartog C et al (2006) Regional and cellular gene expression changes in human Huntington’s disease brain. Hum Mol Genet 15(6):965–977

    CAS  Article  PubMed  Google Scholar 

  21. Luthi-Carter R, Strand A, Peters NL, Solano SM, Hollingsworth ZR, Menon AS, Frey AS, Spektor BS et al (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 9(9):1259–1271

    CAS  Article  PubMed  Google Scholar 

  22. Delacroix L, Moutier E, Altobelli G, Legras S, Poch O, Choukrallah MA, Bertin I, Jost B et al (2010) Cell-specific interaction of retinoic acid receptors with target genes in mouse embryonic fibroblasts and embryonic stem cells. Mol Cell Biol 30(1):231–244

    CAS  Article  PubMed  Google Scholar 

  23. Krebs A, Frontini M, Tora L (2008) GPAT: retrieval of genomic annotation from large genomic position datasets. BMC Bioinformatics 9:533

    Article  PubMed  PubMed Central  Google Scholar 

  24. da Huang W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57

    CAS  Article  Google Scholar 

  25. McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, Wenger AM, Bejerano G (2010) GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol 28(5):495–501

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Mahony S, Mazzoni EO, McCuine S, Young RA, Wichterle H, Gifford DK (2011) Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis. Genome Biol 12(1):R2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Mendoza-Parra MA, Walia M, Sankar M, Gronemeyer H (2011) Dissecting the retinoid-induced differentiation of F9 embryonal stem cells by integrative genomics. Mol Syst Biol 7:538

    Article  PubMed  PubMed Central  Google Scholar 

  28. van den Bogaard SJ, Dumas EM, Acharya TP, Johnson H, Langbehn DR, Scahill RI, Tabrizi SJ, van Buchem MA et al (2011) Early atrophy of pallidum and accumbens nucleus in Huntington’s disease. J Neurol 258(3):412–420

    Article  PubMed  Google Scholar 

  29. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44(6):559–577

    CAS  Article  PubMed  Google Scholar 

  30. Bi J, Hu X, Loh HH, Wei LN (2001) Regulation of mouse kappa opioid receptor gene expression by retinoids. J Neurosci 21(5):1590–1599

    CAS  PubMed  Google Scholar 

  31. Desplats PA, Kass KE, Gilmartin T, Stanwood GD, Woodward EL, Head SR, Sutcliffe JG, Thomas EA (2006) Selective deficits in the expression of striatal-enriched mRNAs in Huntington’s disease. J Neurochem 96(3):743–757

    CAS  Article  PubMed  Google Scholar 

  32. Zetterstrom RH, Lindqvist E, Mata de Urquiza A, Tomac A, Eriksson U, Perlmann T, Olson L (1999) Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acid. Eur J Neurosci 11(2):407–416

    CAS  Article  PubMed  Google Scholar 

  33. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS et al (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445(7124):168–176

    CAS  Article  PubMed  Google Scholar 

  34. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y et al (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87(3):493–506

    CAS  Article  PubMed  Google Scholar 

  35. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C et al (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38(4):576–589

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Mangelsdorf DJ, Umesono K, Kliewer SA, Borgmeyer U, Ong ES, Evans RM (1991) A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR. Cell 66(3):555–561

    CAS  Article  PubMed  Google Scholar 

  37. Nakshatri H, Chambon P (1994) The directly repeated RG(G/T)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites for RAR, RXR, HNF-4, and ARP-1 homo- and heterodimers. J Biol Chem 269(2):890–902

    CAS  PubMed  Google Scholar 

  38. Bastien J, Rochette-Egly C (2004) Nuclear retinoid receptors and the transcription of retinoid-target genes. Gene 328:1–16

    CAS  Article  PubMed  Google Scholar 

  39. Moutier E, Ye T, Choukrallah MA, Urban S, Osz J, Chatagnon A, Delacroix L, Langer D et al (2012) Retinoic acid receptors recognize the mouse genome through binding elements with diverse spacing and topology. J Biol Chem 287(31):26328–26341

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Thomas-Chollier M, Herrmann C, Defrance M, Sand O, Thieffry D, van Helden J (2012) RSAT peak-motifs: motif analysis in full-size ChIP-seq datasets. Nucleic Acids Res 40(4), e31

    CAS  Article  PubMed  Google Scholar 

  41. Juven-Gershon T, Kadonaga JT (2010) Regulation of gene expression via the core promoter and the basal transcriptional machinery. Dev Biol 339(2):225–229

    CAS  Article  PubMed  Google Scholar 

  42. Mukhopadhyay B, Liu J, Osei-Hyiaman D, Godlewski G, Mukhopadhyay P, Wang L, Jeong WI, Gao B et al (2010) Transcriptional regulation of cannabinoid receptor-1 expression in the liver by retinoic acid acting via retinoic acid receptor-gamma. J Biol Chem 285(25):19002–19011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Iniguez MA, Morte B, Rodriguez-Pena A, Munoz A, Gerendasy D, Sutcliffe JG, Bernal J (1994) Characterization of the promoter region and flanking sequences of the neuron-specific gene RC3 (neurogranin). Brain Res Mol Brain Res 27(2):205–214

    CAS  Article  PubMed  Google Scholar 

  44. Everitt BJ, Robbins TW (2013) From the ventral to the dorsal striatum: devolving views of their roles in drug addiction. Neurosci Biobehav Rev 37(9 Pt A):1946–1954

    Article  PubMed  Google Scholar 

  45. Ramirez AD, Smith SM (2014) Regulation of dopamine signaling in the striatum by phosphodiesterase inhibitors: novel therapeutics to treat neurological and psychiatric disorders. Cent Nerv Syst Agents Med Chem 14(2):72–82

    CAS  Article  PubMed  Google Scholar 

  46. Martin AB, Fernandez-Espejo E, Ferrer B, Gorriti MA, Bilbao A, Navarro M, Rodriguez de Fonseca F, Moratalla R (2008) Expression and function of CB1 receptor in the rat striatum: localization and effects on D1 and D2 dopamine receptor-mediated motor behaviors. Neuropsychopharmacology 33(7):1667–1679

    CAS  Article  PubMed  Google Scholar 

  47. Hoppa MB, Lana B, Margas W, Dolphin AC, Ryan TA (2012) Alpha2delta expression sets presynaptic calcium channel abundance and release probability. Nature 486(7401):122–125

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Benoist M, Gaillard S, Castets F (2006) The striatin family: a new signaling platform in dendritic spines. J Physiol Paris 99(2–3):146–153

    CAS  Article  PubMed  Google Scholar 

  49. Huang KP, Huang FL, Jager T, Li J, Reymann KG, Balschun D (2004) Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling. J Neurosci 24(47):10660–10669

    CAS  Article  PubMed  Google Scholar 

  50. Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA et al (1996) A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85(3):403–414

    CAS  Article  PubMed  Google Scholar 

  51. Kurokawa R, Soderstrom M, Horlein A, Halachmi S, Brown M, Rosenfeld MG, Glass CK (1995) Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature 377(6548):451–454

    CAS  Article  PubMed  Google Scholar 

  52. Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP et al (2000) The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci U S A 97(12):6763–6768

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Boutell JM, Thomas P, Neal JW, Weston VJ, Duce J, Harper PS, Jones AL (1999) Aberrant interactions of transcriptional repressor proteins with the Huntington’s disease gene product, huntingtin. Hum Mol Genet 8(9):1647–1655

    CAS  Article  PubMed  Google Scholar 

  54. Mey J, McCaffery P (2004) Retinoic acid signaling in the nervous system of adult vertebrates. Neuroscientist 10(5):409–421

    CAS  Article  PubMed  Google Scholar 

  55. Chaturvedi RK, Flint Beal M (2013) Mitochondrial diseases of the brain. Free Radic Biol Med 63:1–29

    CAS  Article  PubMed  Google Scholar 

  56. Cha JH (2000) Transcriptional dysregulation in Huntington’s disease. Trends Neurosci 23(9):387–392

    CAS  Article  PubMed  Google Scholar 

  57. Zhai W, Jeong H, Cui L, Krainc D, Tjian R (2005) In vitro analysis of huntingtin-mediated transcriptional repression reveals multiple transcription factor targets. Cell 123(7):1241–1253

    CAS  Article  PubMed  Google Scholar 

  58. Shimohata T, Nakajima T, Yamada M, Uchida C, Onodera O, Naruse S, Kimura T, Koide R et al (2000) Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 26(1):29–36

    CAS  Article  PubMed  Google Scholar 

  59. Nucifora FC Jr, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, Takahashi H, Tsuji S et al (2001) Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 291(5512):2423–2428

    CAS  Article  PubMed  Google Scholar 

  60. Dunah AW, Jeong H, Griffin A, Kim YM, Standaert DG, Hersch SM, Mouradian MM, Young AB et al (2002) Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science 296(5576):2238–2243

    CAS  Article  PubMed  Google Scholar 

  61. Li SH, Cheng AL, Zhou H, Lam S, Rao M, Li H, Li XJ (2002) Interaction of Huntington disease protein with transcriptional activator Sp1. Mol Cell Biol 22(5):1277–1287

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Schaffar G, Breuer P, Boteva R, Behrends C, Tzvetkov N, Strippel N, Sakahira H, Siegers K et al (2004) Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell 15(1):95–105

    CAS  Article  PubMed  Google Scholar 

  63. Strand AD, Aragaki AK, Shaw D, Bird T, Holton J, Turner C, Tapscott SJ, Tabrizi SJ et al (2005) Gene expression in Huntington’s disease skeletal muscle: a potential biomarker. Hum Mol Genet 14(13):1863–1876

    CAS  Article  PubMed  Google Scholar 

  64. Kuhn A, Goldstein DR, Hodges A, Strand AD, Sengstag T, Kooperberg C, Becanovic K, Pouladi MA et al (2007) Mutant huntingtin’s effects on striatal gene expression in mice recapitulate changes observed in human Huntington’s disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum Mol Genet 16(15):1845–1861

    CAS  Article  PubMed  Google Scholar 

  65. Chaturvedi RK, Adhihetty P, Shukla S, Hennessy T, Calingasan N, Yang L, Starkov A, Kiaei M et al (2009) Impaired PGC-1alpha function in muscle in Huntington’s disease. Hum Mol Genet 18(16):3048–3065

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Tang B, Becanovic K, Desplats PA, Spencer B, Hill AM, Connolly C, Masliah E, Leavitt BR et al (2012) Forkhead box protein p1 is a transcriptional repressor of immune signaling in the CNS: implications for transcriptional dysregulation in Huntington disease. Hum Mol Genet 21(14):3097–3111

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Benayoun BA, Pollina EA, Ucar D, Mahmoudi S, Karra K, Wong ED, Devarajan K, Daugherty AC et al (2014) H3K4me3 breadth is linked to cell identity and transcriptional consistency. Cell 158(3):673–688

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Ujike H, Takaki M, Nakata K, Tanaka Y, Takeda T, Kodama M, Fujiwara Y, Sakai A et al (2002) CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol Psychiatry 7(5):515–518

    CAS  Article  PubMed  Google Scholar 

  69. Catapano LA, Manji HK (2007) G protein-coupled receptors in major psychiatric disorders. Biochim Biophys Acta 1768(4):976–993

    CAS  Article  PubMed  Google Scholar 

  70. Moreno JL, Holloway T, Gonzalez-Maeso J (2013) G protein-coupled receptor heterocomplexes in neuropsychiatric disorders. Prog Mol Biol Transl Sci 117:187–205

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Hanganu A, Bedetti C, Degroot C, Mejia-Constain B, Lafontaine AL, Soland V, Chouinard S, Bruneau MA et al (2014) Mild cognitive impairment is linked with faster rate of cortical thinning in patients with Parkinson’s disease longitudinally. Brain 137(Pt 4):1120–1129

    Article  PubMed  Google Scholar 

  72. Mavridis I, Boviatsis E, Anagnostopoulou S (2011) The human nucleus accumbens suffers parkinsonism-related shrinkage: a novel finding. Surg Radiol Anat 33(7):595–599

    Article  PubMed  Google Scholar 

  73. Pievani M, Bocchetta M, Boccardi M, Cavedo E, Bonetti M, Thompson PM, Frisoni GB (2013) Striatal morphology in early-onset and late-onset Alzheimer’s disease: a preliminary study. Neurobiol Aging 34(7):1728–1739

    CAS  Article  PubMed  Google Scholar 

  74. Oyama F, Miyazaki H, Sakamoto N, Becquet C, Machida Y, Kaneko K, Uchikawa C, Suzuki T et al (2006) Sodium channel beta4 subunit: down-regulation and possible involvement in neuritic degeneration in Huntington’s disease transgenic mice. J Neurochem 98(2):518–529

    CAS  Article  PubMed  Google Scholar 

  75. Willy PJ, Kobayashi R, Kadonaga JT (2000) A basal transcription factor that activates or represses transcription. Science 290(5493):982–985

    CAS  Article  PubMed  Google Scholar 

  76. Muscat GE, Burke LJ, Downes M (1998) The corepressor N-CoR and its variants RIP13a and RIP13Delta1 directly interact with the basal transcription factors TFIIB, TAFII32 and TAFII70. Nucleic Acids Res 26(12):2899–2907

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Burke TW, Kadonaga JT (1997) The downstream core promoter element, DPE, is conserved from Drosophila to humans and is recognized by TAFII60 of Drosophila. Genes Dev 11(22):3020–3031

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Ghyselinck NB, Dupé V, Dierich A, Messaddeq N, Garnier JM, Rochette-Egly C, Chambon P, Mark M (1997) Role of the retinoic acid receptor beta (RARbeta) during mouse development. Int J Dev Biol 41(3):425–447

    CAS  PubMed  Google Scholar 

  79. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nusbaum C, Myers RM et al (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol 9(9):R137

    Article  PubMed  PubMed Central  Google Scholar 

  80. Ye T, Krebs AR, Choukrallah MA, Keime C, Plewniak F, Davidson I, Tora L (2011) seqMINER: an integrated ChIP-seq data interpretation platform. Nucleic Acids Res 39(6):e35

    CAS  Article  PubMed  Google Scholar 

  81. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102(43):15545–15550

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. Bolstad BM, Irizarry RA, Astrand M, Speed TP (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19(2):185–193

    CAS  Article  PubMed  Google Scholar 

  83. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4(2):249–264

    Article  PubMed  Google Scholar 

  84. Dembele D, Kastner P (2014) Fold change rank ordering statistics: a new method for detecting differentially expressed genes. BMC Bioinformatics 15:14

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by a grant from the Agence Nationale de la Recherche (ANR grant ReSiNEs, ANR-11-BSV2-0003) to P.D. and by an institutional grant (LabEx ANR-10-LABX-0030-INRT) under the frame program Investissements d’Avenir labeled ANR-10-IDEX-0002-02. A.N-C was supported by ReSiNEs and by LabEx INRT funds, and A.P-D. by a PhD fellowship from INRT funds. A.K. was supported by fellowships from the French government (cotutelle), financement relais du Collège Doctoral Européen, and ANR (grant Neuroprotect; ANR-07-PNRA-022-04 to W.K.). We thank C. Thibault-Carpentier, B. Jost, I. Martianov, A. Oravecz, and K. Merienne, for helpful discussions concerning ChIP and transcriptomic analyses; V. Alunni and S. Vicaire from the IGBMC Microarray and High-Throughput Sequencing Platform for processing Affymetrix chips and Illumina libraries, respectively. The Platform is supported by the France Génomique National infrastructure, funded as part of the Investissements d’Avenir program ANR-10-INBS-09. We thank also Y. Trottier and C. Weber for advice on R6/2 line maintenance, P. Kessler from the IGBMC Imaging Platform for assistance in image acquisition and analyses, and V. Fraulob, B. Schuhbaur and J. Sikora for technical assistance.

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Author notes

  1. Agnieszka Krzyżosiak

    Present address: MRC Laboratory of Molecular Biology, Francis Crick Avenue, CB2 0QH, Cambridge, UK

Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404, Illkirch Cedex, France

    Anna Niewiadomska-Cimicka, Agnieszka Krzyżosiak, Tao Ye, Anna Podleśny-Drabiniok, Doulaye Dembélé, Pascal Dollé & Wojciech Krężel

  2. Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France

    Anna Niewiadomska-Cimicka, Agnieszka Krzyżosiak, Tao Ye, Anna Podleśny-Drabiniok, Doulaye Dembélé, Pascal Dollé & Wojciech Krężel

  3. Institut National de la Santé et de la Recherche Médicale, U 964, Illkirch, France

    Anna Niewiadomska-Cimicka, Agnieszka Krzyżosiak, Tao Ye, Anna Podleśny-Drabiniok, Doulaye Dembélé, Pascal Dollé & Wojciech Krężel

  4. Université de Strasbourg, Illkirch, France

    Anna Niewiadomska-Cimicka, Agnieszka Krzyżosiak, Tao Ye, Anna Podleśny-Drabiniok, Doulaye Dembélé, Pascal Dollé & Wojciech Krężel

  5. Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France

    Anna Niewiadomska-Cimicka, Agnieszka Krzyżosiak, Anna Podleśny-Drabiniok, Pascal Dollé & Wojciech Krężel

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  1. Anna Niewiadomska-Cimicka
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Correspondence to Wojciech Krężel.

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ESM 1

Table S1. Genes with RARβ binding sites, which have been reported to be affected in their expression in Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), or schizophrenia (IPA and David analysis). (XLSX 29 kb)

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Table S2. Transcriptional regulators bearing RARβ binding site(s) and which expression was reported to be impaired in HD. (DOCX 16 kb)

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Table S3. Genes with RARβ binding sites, which expression was reported to be affected in transcriptomic analyses of human post-mortem HD caudate nucleus samples (Hodges et al., [20]). (XLSX 34 kb)

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Table S4. Functional annotations of transcriptional changes in the NAcSh of RARβ−/− mice. (XLSX 13 kb)

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Table S5. Genes associated with G-protein signaling and altered in their expression in the NAcSh of RARβ−/− mice (IPA analysis). (DOCX 15 kb)

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Table S6. Genes which expression was reported to be affected in transcriptomic analyses of human post-mortem HD caudate nucleus samples (Hodges et al. [20]) as well as in NAcSh of RARβ−/− mice (this study). The following criteria were applied for both transcriptomes: 0.80 ≥ fold change (FC) ≥1.20, p value ≤0.05. (XLSX 17 kb)

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Table S7. Genes bearing RARβ binding sites and which expression was significantly altered in transcriptomic analyses of the RARβ−/− NAcSh. The following criteria were applied: 0.80 ≥ fold change (FC) ≥1.20, p value ≤0.05. (DOCX 29 kb)

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Fig. S1. Validation of specificity of the anti-RARβ antibody. RARβ (red) can be visualized by immunofluorescence detection in coronal sections of WT (A), but not RARβ−/− (B) CPu. Nuclei are counterstained with DAPI (blue). Scale bar, 10 μm. (JPG 90 kb)

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Fig. S2. Analysis of RARβ expression in the striatum of R6/2 mice embryos at stage E16.5. Immunofluorescent detection of RARβ (red) and HTT (green) in coronal sections of the CPu in E16.5 WT (upper panels) and R6/2 transgenic mice (lower panels). DAPI stained nuclei are shown in blue. Scale bar, 10 μm. (JPG 498 kb)

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Fig. S3. The statistical significance of cluster 1, cluster 2, and cluster 3-bound gene groups from comparative clustering of RARβ and H3K4me3 read densities (see Fig. 4d). Bootstrap statistical analyses (see Materials and Methods) were carried out with a random selection of 6273 genes (IDs) out of a total pool of 26,460 ENSEMBL IDs. Histograms represent the average numbers of observed IDs in the three random sets. The average numbers and SDs are: cluster 1, 245 ± 16 (A); cluster 2, 610 ± 21 (B); and cluster 3, 483 ± 21 (C). These averages are significantly far from the experimentally determined numbers (p value < 1.0e−32) shown with an arrow in bold. The z-cores are 51.26 (cluster 1), 93.01 (cluster 2), and 104.01 (cluster 3). (JPG 194 kb)

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Table S8. List of primers used for qPCR analyses. (DOCX 17 kb)

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Niewiadomska-Cimicka, A., Krzyżosiak, A., Ye, T. et al. Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington’s Disease and Other Neurodegenerative Disorders. Mol Neurobiol 54, 3859–3878 (2017). https://doi.org/10.1007/s12035-016-0010-4

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  • DOI: https://doi.org/10.1007/s12035-016-0010-4

Keywords

  • Retinoic acid
  • RAR
  • Huntington’s disease
  • Striatum
  • Nucleus accumbens
  • Response elements
  • ChIP-seq
  • Transcriptome