Transcriptional Regulation of Rod Photoreceptor Homeostasis Revealed by NRL Targetome Analysis
A stringent control of homeostasis is critical for functional maintenance and survival of neurons. In the mammalian retina, the basic motif leucine zipper transcription factor NRL determines rod versus cone photoreceptor cell fate and activates the expression of many rod-specific genes. Here, we report an integrated analysis of NRL-centered gene regulatory network by coupling chromatin immunoprecipitation followed by high-throughput sequencing (ChIP–Seq) data from Illumina and ABI platforms with global expression profiling and in vivo knockdown studies. We identified approximately 300 direct NRL target genes. Of these, 22 NRL targets are associated with human retinal dystrophies, whereas 95 mapped to regions of as yet uncloned retinal disease loci. In silico analysis of NRL ChIP–Seq peak sequences revealed an enrichment of distinct sets of transcription factor binding sites. Specifically, we discovered that genes involved in photoreceptor function include binding sites for both NRL and homeodomain protein CRX. Evaluation of 26 ChIP–Seq regions validated their enhancer functions in reporter assays. In vivo knockdown of 16 NRL target genes resulted in death or abnormal morphology of rod photoreceptors, suggesting their importance in maintaining retinal function. We also identified histone demethylase Kdm5b as a novel secondary node in NRL transcriptional hierarchy. Exon array analysis of flow-sorted photoreceptors in which Kdm5b was knocked down by shRNA indicated its role in regulating rod-expressed genes. Our studies identify candidate genes for retinal dystrophies, define cis-regulatory module(s) for photoreceptor-expressed genes and provide a framework for decoding transcriptional regulatory networks that dictate rod homeostasis.
Vyšlo v časopise:
Transcriptional Regulation of Rod Photoreceptor Homeostasis Revealed by NRL Targetome Analysis. PLoS Genet 8(4): e32767. doi:10.1371/journal.pgen.1002649
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002649
Souhrn
A stringent control of homeostasis is critical for functional maintenance and survival of neurons. In the mammalian retina, the basic motif leucine zipper transcription factor NRL determines rod versus cone photoreceptor cell fate and activates the expression of many rod-specific genes. Here, we report an integrated analysis of NRL-centered gene regulatory network by coupling chromatin immunoprecipitation followed by high-throughput sequencing (ChIP–Seq) data from Illumina and ABI platforms with global expression profiling and in vivo knockdown studies. We identified approximately 300 direct NRL target genes. Of these, 22 NRL targets are associated with human retinal dystrophies, whereas 95 mapped to regions of as yet uncloned retinal disease loci. In silico analysis of NRL ChIP–Seq peak sequences revealed an enrichment of distinct sets of transcription factor binding sites. Specifically, we discovered that genes involved in photoreceptor function include binding sites for both NRL and homeodomain protein CRX. Evaluation of 26 ChIP–Seq regions validated their enhancer functions in reporter assays. In vivo knockdown of 16 NRL target genes resulted in death or abnormal morphology of rod photoreceptors, suggesting their importance in maintaining retinal function. We also identified histone demethylase Kdm5b as a novel secondary node in NRL transcriptional hierarchy. Exon array analysis of flow-sorted photoreceptors in which Kdm5b was knocked down by shRNA indicated its role in regulating rod-expressed genes. Our studies identify candidate genes for retinal dystrophies, define cis-regulatory module(s) for photoreceptor-expressed genes and provide a framework for decoding transcriptional regulatory networks that dictate rod homeostasis.
Zdroje
1. PeterISDavidsonEH 2011 Evolution of gene regulatory networks controlling body plan development. Cell 144 970 985
2. LevineMTjianR 2003 Transcription regulation and animal diversity. Nature 424 147 151
3. LevineMDavidsonEH 2005 Gene regulatory networks for development. Proc Natl Acad Sci U S A 102 4936 4942
4. RamockiMBZoghbiHY 2008 Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455 912 918
5. MorrisonJHHofPR 1997 Life and death of neurons in the aging brain. Science 278 412 419
6. LuoDGXueTYauKW 2008 How vision begins: an odyssey. Proc Natl Acad Sci U S A 105 9855 9862
7. BramallANWrightAFJacobsonSGMcInnesRR 2010 The genomic, biochemical, and cellular responses of the retina in inherited photoreceptor degenerations and prospects for the treatment of these disorders. Annu Rev Neurosci 33 441 472
8. LambTDCollinSPPughENJr 2007 Evolution of the vertebrate eye: opsins, photoreceptors, retina and eye cup. Nat Rev Neurosci 8 960 976
9. JacksonGROwsleyCCurcioCA 2002 Photoreceptor degeneration and dysfunction in aging and age-related maculopathy. Ageing research reviews 1 381 396
10. WrightAFChakarovaCFAbd El-AzizMMBhattacharyaSS 2010 Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat Rev Genet 11 273 284
11. SwaroopAKimDForrestD 2010 Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina. Nat Rev Neurosci 11 563 576
12. LiveseyFJCepkoCL 2001 Vertebrate neural cell-fate determination: lessons from the retina. Nat Rev Neurosci 2 109 118
13. AgathocleousMHarrisWA 2009 From progenitors to differentiated cells in the vertebrate retina. Annu Rev Cell Dev Biol 25 45 69
14. MearsAJKondoMSwainPKTakadaYBushRA 2001 Nrl is required for rod photoreceptor development. Nat Genet 29 447 452
15. OhECKhanNNovelliEKhannaHStrettoiE 2007 Transformation of cone precursors to functional rod photoreceptors by bZIP transcription factor NRL. Proc Natl Acad Sci U S A 104 1679 1684
16. NgLLuASwaroopASharlinDSForrestD 2011 Two transcription factors can direct three photoreceptor outcomes from rod precursor cells in mouse retinal development. J Neurosci 31 11118 11125
17. ChengHAlemanTSCideciyanAVKhannaRJacobsonSG 2006 In vivo function of the orphan nuclear receptor NR2E3 in establishing photoreceptor identity during mammalian retinal development. Hum Mol Genet 15 2588 2602
18. ChenJRattnerANathansJ 2005 The rod photoreceptor-specific nuclear receptor Nr2e3 represses transcription of multiple cone-specific genes. J Neurosci 25 118 129
19. PengGHAhmadOAhmadFLiuJChenS 2005 The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx and exerts opposing effects on the transcription of rod versus cone genes. Hum Mol Genet 14 747 764
20. FurukawaTMorrowEMLiTDavisFCCepkoCL 1999 Retinopathy and attenuated circadian entrainment in Crx-deficient mice. Nat Genet 23 466 470
21. HennigAKPengGHChenS 2008 Regulation of photoreceptor gene expression by Crx-associated transcription factor network. Brain Res 1192 114 133
22. CorboJCLawrenceKAKarlstetterMMyersCAAbdelazizM 2010 CRX ChIP–Seq reveals the cis-regulatory architecture of mouse photoreceptors. Genome Res 20 1512 1525
23. BrooksMJRajasimhaHKRogerJESwaroopA 2011 Next generation sequencing facilitates quantitative analysis of wild type and Nrl−/− retinal transcriptomes. Mol Vis in press
24. MittonKPSwainPKChenSXuSZackDJ 2000 The leucine zipper of NRL interacts with the CRX homeodomain. A possible mechanism of transcriptional synergy in rhodopsin regulation. J Biol Chem 275 29794 29799
25. AkimotoMChengHZhuDBrzezinskiJAKhannaR 2006 Targeting of GFP to newborn rods by Nrl promoter and temporal expression profiling of flow-sorted photoreceptors. Proc Natl Acad Sci U S A 103 3890 3895
26. CorboJCMyersCALawrenceKAJadhavAPCepkoCL 2007 A typology of photoreceptor gene expression patterns in the mouse. Proc Natl Acad Sci U S A 104 12069 12074
27. YoshidaSMearsAJFriedmanJSCarterTHeS 2004 Expression profiling of the developing and mature Nrl−/− mouse retina: identification of retinal disease candidates and transcriptional regulatory targets of Nrl. Hum Mol Genet 13 1487 1503
28. ZhangYLiuTMeyerCAEeckhouteJJohnsonDS 2008 Model-based analysis of ChIP–Seq (MACS). Genome Biol 9 R137
29. PtashneM 2005 Regulation of transcription: from lambda to eukaryotes. Trends Biochem Sci 30 275 279
30. PtashneMGannA 1997 Transcriptional activation by recruitment. Nature 386 569 577
31. QuandtKFrechKKarasHWingenderEWernerT 1995 MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. Nucleic Acids Res 23 4878 4884
32. CarthariusKFrechKGroteKKlockeBHaltmeierM 2005 MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 21 2933 2942
33. ChenSWangQLNieZSunHLennonG 1997 Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes. Neuron 19 1017 1030
34. ChengHKhannaHOhECHicksDMittonKP 2004 Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors. Hum Mol Genet 13 1563 1575
35. HaiderNBJacobsonSGCideciyanAVSwiderskiRStrebLM 2000 Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet 24 127 131
36. JiaLOhECNgLSrinivasMBrooksM 2009 Retinoid-related orphan nuclear receptor RORbeta is an early-acting factor in rod photoreceptor development. Proc Natl Acad Sci U S A 106 17534 17539
37. SrinivasMNgLLiuHJiaLForrestD 2006 Activation of the blue opsin gene in cone photoreceptor development by retinoid-related orphan receptor beta. Mol Endocrinol 20 1728 1741
38. OnishiAPengGHPothEMLeeDAChenJ 2010 The orphan nuclear hormone receptor ERRbeta controls rod photoreceptor survival. Proc Natl Acad Sci U S A 107 11579 11584
39. HaoHTummalaPGuzmanEMaliRSGregorskiJ 2011 The transcription factor NRL controls photoreceptor-specific expression of myocyte enhancer factor Mef2c from an alternative promoter. J Biol Chem
40. HsiauTHDiaconuCMyersCALeeJCepkoCL 2007 The cis-regulatory logic of the mammalian photoreceptor transcriptional network. PLoS One 2 e643
41. OhECChengHHaoHJiaLKhanNW 2008 Rod differentiation factor NRL activates the expression of nuclear receptor NR2E3 to suppress the development of cone photoreceptors. Brain Res 1236 16 29
42. RehemtullaAWarwarRKumarRJiXZackDJ 1996 The basic motif-leucine zipper transcription factor Nrl can positively regulate rhodopsin gene expression. Proc Natl Acad Sci U S A 93 191 195
43. KumarRChenSScheurerDWangQLDuhE 1996 The bZIP transcription factor Nrl stimulates rhodopsin promoter activity in primary retinal cell cultures. J Biol Chem 271 29612 29618
44. KautzmannMAKimDSFelder-SchmittbuhlMPSwaroopA 2011 Combinatorial regulation of photoreceptor differentiation factor, neural retina leucine zipper gene NRL, revealed by in vivo promoter analysis. J Biol Chem 286 28247 28255
45. MatsudaTCepkoCL 2004 Electroporation and RNA interference in the rodent retina in vivo and in vitro. Proc Natl Acad Sci U S A 101 16 22
46. Carter-DawsonLDLaVailMM 1979 Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy. J Comp Neurol 188 245 262
47. SecombeJEisenmanRN 2007 The function and regulation of the JARID1 family of histone H3 lysine 4 demethylases: the Myc connection. Cell Cycle 6 1324 1328
48. KrishnakumarRKrausWL 2010 PARP-1 regulates chromatin structure and transcription through a KDM5B-dependent pathway. Mol Cell 39 736 749
49. YamaneKTateishiKKloseRJFangJFabrizioLA 2007 PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. Mol Cell 25 801 812
50. HollanderMCSheikhMSBulavinDVLundgrenKAugeri-HenmuellerL 1999 Genomic instability in Gadd45a-deficient mice. Nat Genet 23 176 184
51. HardySJacquesPEGevryNForestAFortinME 2009 The euchromatic and heterochromatic landscapes are shaped by antagonizing effects of transcription on H2A.Z deposition. PLoS Genet 5 e1000687
52. PetersAHO'CarrollDScherthanHMechtlerKSauerS 2001 Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107 323 337
53. PittlerSJZhangYChenSMearsAJZackDJ 2004 Functional analysis of the rod photoreceptor cGMP phosphodiesterase alpha-subunit gene promoter: Nrl and Crx are required for full transcriptional activity. J Biol Chem 279 19800 19807
54. LernerLEGribanovaYEJiMKnoxBEFarberDB 2001 Nrl and Sp nuclear proteins mediate transcription of rod-specific cGMP-phosphodiesterase beta-subunit gene: involvement of multiple response elements. J Biol Chem 276 34999 35007
55. BarskiACuddapahSCuiKRohTYSchonesDE 2007 High-resolution profiling of histone methylations in the human genome. Cell 129 823 837
56. JohnsonDSMortazaviAMyersRMWoldB 2007 Genome-wide mapping of in vivo protein-DNA interactions. Science 316 1497 1502
57. WangZZangCCuiKSchonesDEBarskiA 2009 Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138 1019 1031
58. FujiwaraTO'GeenHKelesSBlahnikKLinnemannAK 2009 Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy. Mol Cell 36 667 681
59. ShendureJJiH 2008 Next-generation DNA sequencing. Nat Biotechnol 26 1135 1145
60. ParkPJ 2009 ChIP–Seq: advantages and challenges of a maturing technology. Nat Rev Genet 10 669 680
61. MuranishiYSatoSInoueTUenoSKoyasuT 2010 Gene expression analysis of embryonic photoreceptor precursor cells using BAC-Crx-EGFP transgenic mouse. Biochem Biophys Res Comm 392 317 322
62. PengGHChenS 2007 Crx activates opsin transcription by recruiting HAT-containing co-activators and promoting histone acetylation. Hum Mol Genet 16 2433 2452
63. PeterISDavidsonEH 2011 A gene regulatory network controlling the embryonic specification of endoderm. Nature 474 635 639
64. SmithJTheodorisCDavidsonEH 2007 A gene regulatory network subcircuit drives a dynamic pattern of gene expression. Science 318 794 797
65. RisterJDesplanC 2010 Deciphering the genome's regulatory code: the many languages of DNA. Bio Essays 32 381 384
66. XieLPelzCWangWBasharAVarlamovaO 2011 KDM5B regulates embryonic stem cell self-renewal and represses cryptic intragenic transcription. EMBO J 30 1473 1484
67. SoloveiIKreysingMLanctotCKosemSPeichlL 2009 Nuclear architecture of rod photoreceptor cells adapts to vision in mammalian evolution. Cell 137 356 368
68. MustafiDKevanyBMGenoudCOkanoKCideciyanAV 2011 Defective photoreceptor phagocytosis in a mouse model of enhanced S-cone syndrome causes progressive retinal degeneration. FASEB J 25 3157 3176
69. NicholsWCGinsburgD 1999 From the ER to the golgi: insights from the study of combined factors V and VIII deficiency. Am J Hum Genet 64 1493 1498
70. XuLCorcoranRBWelshJWPennicaDLevineAJ 2000 WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene. Genes Dev 14 585 595
71. VenkatesanBPrabhuSDVenkatachalamKMummidiSValenteAJ 2010 WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death. Cell Signal 22 809 820
72. SuFOverholtzerMBesserDLevineAJ 2002 WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase. Genes Dev 16 46 57
73. Ben-Tabou de-LeonSDavidsonEH 2007 Gene regulation: gene control network in development. Annu Rev Biophys Biomol Struct 36 191
74. BoyadjievSAJabsEW 2000 Online Mendelian Inheritance in Man (OMIM) as a knowledgebase for human developmental disorders. Clin Genet 57 253 266
75. VaquerizasJMKummerfeldSKTeichmannSALuscombeNM 2009 A census of human transcription factors: function, expression and evolution. Nat Rev Genet 10 252 263
76. HughesJDEstepPWTavazoieSChurchGM 2000 Computational identification of cis-regulatory elements associated with groups of functionally related genes in Saccharomyces cerevisiae. J Mol Biol 296 1205 1214
77. ZipperHBrunnerHBernhagenJVitzthumF 2004 Investigations on DNA intercalation and surface binding by SYBR Green I, its structure determination and methodological implications. Nucleic Acids Res 32 e103
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Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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