Combined serial analysis of gene expression and transcription factor binding site prediction identifies novel-candidate-target genes of Nr2e1 in neocortex development

BMC Genomics

Wyeth W. Wasserman²  Elizabeth M. Simpson¹  Marco A. Marra²  Steven J. M. Jones²  Siaw H. Wong⁴  Russell J. Bonaguro⁴  Kathleen G. Banks⁴  Slavita Bohacec⁴  Yuan-Yun Xie⁴  Ximena Corso-Díaz³  David Arenillas⁴  Jean-François Schmouth⁵ 

[1] Department of Psychiatry, University of British Columbia, Vancouver V6T 2A1, BC, Canada;Department of Medical Genetics, University of British Columbia, Vancouver V6T 1Z3, BC, Canada;Genetics Graduate Program, University of British Columbia, Vancouver V6T 1Z2, BC, Canada;Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver V5Z 4H4, BC, Canada;Current address: Montreal Neurological Institute and Hospital, McGill University, Montréal H3A 2B4, QC, Canada

关键词: Transcription factor;    Neocortex;    Transcriptome;    Nr2e1;    Nuclear receptor;    SAGE;   

Others  :  1221883
DOI  :  10.1186/s12864-015-1770-3

 received in 2014-12-10, accepted in 2015-07-13,  发布年份 2015

【 摘 要 】

Background

Nr2e1 (nuclear receptor subfamily 2, group e, member 1) encodes a transcription factor important in neocortex development. Previous work has shown that nuclear receptors can have hundreds of target genes, and bind more than 300 co-interacting proteins. However, recognition of the critical role of Nr2e1 in neural stem cells and neocortex development is relatively recent, thus the molecular mechanisms involved for this nuclear receptor are only beginning to be understood. Serial analysis of gene expression (SAGE), has given researchers both qualitative and quantitative information pertaining to biological processes. Thus, in this work, six LongSAGE mouse libraries were generated from laser microdissected tissue samples of dorsal VZ/SVZ (ventricular zone and subventricular zone) from the telencephalon of wild-type (Wt) and Nr2e1-null embryos at the critical development ages E13.5, E15.5, and E17.5. We then used a novel approach, implementing multiple computational methods followed by biological validation to further our understanding of Nr2e1 in neocortex development.

Results

In this work, we have generated a list of 1279 genes that are differentially expressed in response to altered Nr2e1 expression during in vivo neocortex development. We have refined this list to 64 candidate direct-targets of NR2E1. Our data suggested distinct roles for Nr2e1 during different neocortex developmental stages. Most importantly, our results suggest a possible novel pathway by which Nr2e1 regulates neurogenesis, which includes Lhx2 as one of the candidate direct-target genes, and SOX9 as a co-interactor.

Conclusions

In conclusion, we have provided new candidate interacting partners and numerous well-developed testable hypotheses for understanding the pathways by which Nr2e1 functions to regulate neocortex development.

【 授权许可】

   
2015 Schmouth et al.

【 图 表 】

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【 参考文献 】

• [1]Anderson SA, Eisenstat DD, Shi L, Rubenstein JL. Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. Science. 1997; 278:474-6.
• [2]Angevine JB, Sidman RL. Autoradiographic study of cell migration during histogenesis of cerebral cortex in the mouse. Nature. 1961; 192:766-8.
• [3]de Carlos JA, Lopez-Mascaraque L, Valverde F. Dynamics of cell migration from the lateral ganglionic eminence in the rat. J Neurosci. 1996; 16:6146-56.
• [4]Nadarajah B, Brunstrom JE, Grutzendler J, Wong RO, Pearlman AL. Two modes of radial migration in early development of the cerebral cortex. Nat Neurosci. 2001; 4:143-50.
• [5]Tamamaki N, Fujimori KE, Takauji R. Origin and route of tangentially migrating neurons in the developing neocortical intermediate zone. J Neurosci. 1997; 17:8313-23.
• [6]Bayer SA, Altman J. Neocortical development. Raven, New York; 1991.
• [7]Miller FD, Gauthier AS. Timing is everything: making neurons versus glia in the developing cortex. Neuron. 2007; 54:357-69.
• [8]Job C, Tan SS. Constructing the mammalian neocortex: the role of intrinsic factors. Dev Biol. 2003; 257:221-32.
• [9]Roy K, Kuznicki K, Wu Q, Sun Z, Bock D, Schutz G et al.. The Tlx gene regulates the timing of neurogenesis in the cortex. J Neurosci. 2004; 24:8333-45.
• [10]Land PW, Monaghan AP. Expression of the transcription factor, tailless, is required for formation of superficial cortical layers. Cereb Cortex. 2003; 13:921-31.
• [11]Li W, Sun G, Yang S, Qu Q, Nakashima K, Shi Y. Nuclear receptor TLX regulates cell cycle progression in neural stem cells of the developing brain. Mol Endocrinol. 2008; 22:56-64.
• [12]Shi Y, Chichung Lie D, Taupin P, Nakashima K, Ray J, Yu RT et al.. Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature. 2004; 427:78-83.
• [13]Zhang CL, Zou Y, He W, Gage FH, Evans RM. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature. 2008; 451:1004-7.
• [14]Sun G, Yu RT, Evans RM, Shi Y. Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation. Proc Natl Acad Sci U S A. 2007; 104:15282-7.
• [15]Biddie SC, John S. Minireview: conversing with chromatin: the language of nuclear receptors. Mol Endocrinol. 2014; 28:3-15.
• [16]Lonard DM, O’Malley BW. Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation. Mol Cell. 2007; 27:691-700.
• [17]Lonard DM, Lanz RB, O’Malley BW. Nuclear receptor coregulators and human disease. Endocr Rev. 2007; 28:575-87.
• [18]Monaghan AP, Grau E, Bock D, Schutz G. The mouse homolog of the orphan nuclear receptor tailless is expressed in the developing forebrain. Development. 1995; 121:839-53.
• [19]Monaghan AP, Bock D, Gass P, Schwager A, Wolfer DP, Lipp HP et al.. Defective limbic system in mice lacking the tailless gene. Nature. 1997; 390:515-7.
• [20]Young KA, Berry ML, Mahaffey CL, Saionz JR, Hawes NL, Chang B et al.. Fierce: a new mouse deletion of Nr2e1; violent behaviour and ocular abnormalities are background-dependent. Behav Brain Res. 2002; 132:145-58.
• [21]Yokoyama A, Takezawa S, Schule R, Kitagawa H, Kato S. Transrepressive function of TLX requires the histone demethylase LSD1. Mol Cell Biol. 2008; 28:3995-4003.
• [22]Zhao C, Sun G, Li S, Shi Y. A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nat Struct Mol Biol. 2009; 16:365-71.
• [23]Sun G, Ye P, Murai K, Lang MF, Li S, Zhang H et al.. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat Commun. 2011; 2:529.
• [24]Zhao C, Sun G, Ye P, Li S, Shi Y. MicroRNA let-7d regulates the TLX/microRNA-9 cascade to control neural cell fate and neurogenesis. Sci Rep. 2013; 3:1329.
• [25]Iwahara N, Hisahara S, Hayashi T, Horio Y. Transcriptional activation of NAD + −dependent protein deacetylase SIRT1 by nuclear receptor TLX. Biochem Biophys Res Commun. 2009; 386:671-5.
• [26]Hisahara S, Chiba S, Matsumoto H, Tanno M, Yagi H, Shimohama S et al.. Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation. Proc Natl Acad Sci U S A. 2008; 105:15599-604.
• [27]Velculescu VE, Zhang L, Vogelstein B, Kinzler KW. Serial analysis of gene expression. Science. 1995; 270:484-7.
• [28]Hanriot L, Keime C, Gay N, Faure C, Dossat C, Wincker P et al.. A combination of LongSAGE with Solexa sequencing is well suited to explore the depth and the complexity of transcriptome. BMC Genomics. 2008; 9:418. BioMed Central Full Text
• [29]Gunnersen JM, Augustine C, Spirkoska V, Kim M, Brown M, Tan SS. Global analysis of gene expression patterns in developing mouse neocortex using serial analysis of gene expression. Mol Cell Neurosci. 2002; 19:560-73.
• [30]Koehl A, Schmidt N, Rieger A, Pilgram SM, Letunic I, Bork P et al.. Gene expression profiling of the rat superior olivary complex using serial analysis of gene expression. Eur J Neurosci. 2004; 20:3244-58.
• [31]D’Souza CA, Chopra V, Varhol R, Xie YY, Bohacec S, Zhao Y et al.. Identification of a set of genes showing regionally enriched expression in the mouse brain. BMC Neurosci. 2008; 9:66. BioMed Central Full Text
• [32]Popesco MC, Frostholm A, Rejniak K, Rotter A. Digital transcriptome analysis in the aging cerebellum. Ann N Y Acad Sci. 2004; 1019:58-63.
• [33]Ouchi Y, Kubota Y, Ito C. Serial analysis of gene expression in methamphetamine- and phencyclidine-treated rodent cerebral cortices: are there common mechanisms? Ann N Y Acad Sci. 2004; 1025:57-61.
• [34]Guipponi M, Li QX, Hyde L, Beissbarth T, Smyth GK, Masters CL et al.. SAGE analysis of genes differentially expressed in presymptomatic TgSOD1G93A transgenic mice identified cellular processes involved in early stage of ALS pathology. J Mol Neurosci. 2010; 41:172-82.
• [35]Mazarei G, Neal SJ, Becanovic K, Luthi-Carter R, Simpson EM, Leavitt BR. Expression analysis of novel striatal-enriched genes in Huntington disease. Hum Mol Genet. 2010; 19:609-22.
• [36]George AJ, Gordon L, Beissbarth T, Koukoulas I, Holsinger RM, Perreau V et al.. A serial analysis of gene expression profile of the Alzheimer’s disease Tg2576 mouse model. Neurotox Res. 2010; 17:360-79.
• [37]Peters DG, Kassam AB, Yonas H, O’Hare EH, Ferrell RE, Brufsky AM. Comprehensive transcript analysis in small quantities of mRNA by SAGE-lite. Nucleic Acids Res. 1999; 27:e39.
• [38]Wahl MB, Heinzmann U, Imai K. LongSAGE analysis significantly improves genome annotation: identifications of novel genes and alternative transcripts in the mouse. Bioinformatics. 2005; 21:1393-400.
• [39]Ho Sui SJ, Fulton DL, Arenillas DJ, Kwon AT, Wasserman WW. oPOSSUM: integrated tools for analysis of regulatory motif over-representation. Nucleic Acids Res. 2007; 35:W245-52.
• [40]Ho Sui SJ, Mortimer JR, Arenillas DJ, Brumm J, Walsh CJ, Kennedy BP et al.. oPOSSUM: identification of over-represented transcription factor binding sites in co-expressed genes. Nucleic Acids Res. 2005; 33:3154-64.
• [41]Das MK, Dai HK. A survey of DNA motif finding algorithms. BMC Bioinformatics. 2007; 8 Suppl 7:S21. BioMed Central Full Text
• [42]Wasserman WW, Sandelin A. Applied bioinformatics for the identification of regulatory elements. Nat Rev Genet. 2004; 5:276-87.
• [43]Stenman JM, Wang B, Campbell K. Tlx controls proliferation and patterning of lateral telencephalic progenitor domains. J Neurosci. 2003; 23:10568-76.
• [44]Robertson N, Oveisi-Fordorei M, Zuyderduyn SD, Varhol RJ, Fjell C, Marra M et al.. DiscoverySpace: an interactive data analysis application. Genome Biol. 2007; 8:R6. BioMed Central Full Text
• [45]Romanuik TL, Wang G, Holt RA, Jones SJ, Marra MA, Sadar MD. Identification of novel androgen-responsive genes by sequencing of LongSAGE libraries. BMC Genomics. 2009; 10:476. BioMed Central Full Text
• [46]Audic S, Claverie JM. The significance of digital gene expression profiles. Genome Res. 1997; 7:986-95.
• [47]de Hoon MJ, Imoto S, Nolan J, Miyano S. Open source clustering software. Bioinformatics. 2004; 20:1453-4.
• [48]Saldanha AJ. Java Treeview--extensible visualization of microarray data. Bioinformatics. 2004; 20:3246-8.
• [49]Portales-Casamar E, Arenillas D, Lim J, Swanson MI, Jiang S, McCallum A et al.. The PAZAR database of gene regulatory information coupled to the ORCA toolkit for the study of regulatory sequences. Nucleic Acids Res. 2009; 37:D54-60.
• [50]da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4:44-57.
• [51]Dennis G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC et al.. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 2003; 4:P3. BioMed Central Full Text
• [52]Portales-Casamar E, Kirov S, Lim J, Lithwick S, Swanson MI, Ticoll A et al.. PAZAR: a framework for collection and dissemination of cis-regulatory sequence annotation. Genome Biol. 2007; 8:R207. BioMed Central Full Text
• [53]Yu RT, Chiang MY, Tanabe T, Kobayashi M, Yasuda K, Evans RM et al.. The orphan nuclear receptor Tlx regulates Pax2 and is essential for vision. Proc Natl Acad Sci U S A. 2000; 97:2621-5.
• [54]Zhang CL, Zou Y, Yu RT, Gage FH, Evans RM. Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. Genes Dev. 2006; 20:1308-20.
• [55]Qu Q, Sun G, Li W, Yang S, Ye P, Zhao C et al.. Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal. Nat Cell Biol. 2010; 12:31-40.
• [56]Yu RT, McKeown M, Evans RM, Umesono K. Relationship between Drosophila gap gene tailless and a vertebrate nuclear receptor Tlx. Nature. 1994; 370:375-9.
• [57]Hubisz MJ, Pollard KS, Siepel A. PHAST and RPHAST: phylogenetic analysis with space/time models. Brief Bioinform. 2011; 12:41-51.
• [58]Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K et al.. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005; 15:1034-50.
• [59]Sherman BT, Huang da W, Tan Q, Guo Y, Bour S, Liu D et al.. DAVID Knowledgebase: a gene-centered database integrating heterogeneous gene annotation resources to facilitate high-throughput gene functional analysis. BMC Bioinformatics. 2007; 8:426. BioMed Central Full Text
• [60]da Huang W, Sherman BT, Tan Q, Kir J, Liu D, Bryant D et al.. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 2007; 35:W169-75.
• [61]Hosack DA, Dennis G, Sherman BT, Lane HC, Lempicki RA. Identifying biological themes within lists of genes with EASE. Genome Biol. 2003; 4:R70. BioMed Central Full Text
• [62]da Huang W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009; 37:1-13.
• [63]Falcon S, Gentleman R. Using GOstats to test gene lists for GO term association. Bioinformatics. 2007; 23:257-8.
• [64]Shimozaki K, Zhang CL, Suh H, Denli AM, Evans RM, Gage FH. SRY-box-containing gene 2 regulation of nuclear receptor tailless (Tlx) transcription in adult neural stem cells. J Biol Chem. 2012; 287:5969-78.
• [65]Schuurmans C, Armant O, Nieto M, Stenman JM, Britz O, Klenin N et al.. Sequential phases of cortical specification involve Neurogenin-dependent and -independent pathways. Embo J. 2004; 23:2892-902.
• [66]Stenman J, Yu RT, Evans RM, Campbell K. Tlx and Pax6 co-operate genetically to establish the pallio-subpallial boundary in the embryonic mouse telencephalon. Development. 2003; 130:1113-22.
• [67]Peng GH, Ahmad O, Ahmad F, Liu J, Chen S. The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx and exerts opposing effects on the transcription of rod versus cone genes. Hum Mol Genet. 2005; 14:747-64.
• [68]Aranguren XL, Beerens M, Coppiello G, Wiese C, Vandersmissen I, Lo Nigro A et al.. COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1. J Cell Sci. 2013; 126:1164-75.
• [69]Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A et al.. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007; 445:168-76.
• [70]Scott CE, Wynn SL, Sesay A, Cruz C, Cheung M, Gomez Gaviro MV et al.. SOX9 induces and maintains neural stem cells. Nat Neurosci. 2010; 13:1181-9.
• [71]Chou SJ, Perez-Garcia CG, Kroll TT, O’Leary DD. Lhx2 specifies regional fate in Emx1 lineage of telencephalic progenitors generating cerebral cortex. Nat Neurosci. 2009; 12:1381-9.
• [72]Subramanian L, Sarkar A, Shetty AS, Muralidharan B, Padmanabhan H, Piper M et al.. Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus. Proc Natl Acad Sci U S A. 2011; 108:E265-74.
• [73]Chou SJ, O’Leary DD. Role for Lhx2 in corticogenesis through regulation of progenitor differentiation. Mol Cell Neurosci. 2013; 56:1-9.
• [74]Gaspard N, Bouschet T, Herpoel A, Naeije G, van den Ameele J, Vanderhaeghen P. Generation of cortical neurons from mouse embryonic stem cells. Nat Protoc. 2009; 4:1454-63.
• [75]Gaspard N, Bouschet T, Hourez R, Dimidschstein J, Naeije G, van den Ameele J et al.. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature. 2008; 455:351-7.
• [76]Stolt CC, Lommes P, Sock E, Chaboissier MC, Schedl A, Wegner M. The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes Dev. 2003; 17:1677-89.
• [77]Castillo SD, Sanchez-Cespedes M. The SOX family of genes in cancer development: biological relevance and opportunities for therapy. Expert Opin Ther Targets. 2012; 16:903-19.
• [78]Kiefer JC. Back to basics: sox genes. Dev Dyn. 2007; 236:2356-66.
• [79]Pevny L, Placzek M. SOX genes and neural progenitor identity. Curr Opin Neurobiol. 2005; 15:7-13.
• [80]Kwan KY, Lam MM, Krsnik Z, Kawasawa YI, Lefebvre V, Sestan N. SOX5 postmitotically regulates migration, postmigratory differentiation, and projections of subplate and deep-layer neocortical neurons. Proc Natl Acad Sci U S A. 2008; 105:16021-6.
• [81]Sansom SN, Griffiths DS, Faedo A, Kleinjan DJ, Ruan Y, Smith J et al.. The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis. PLoS Genet. 2009; 5:e1000511.
• [82]Khattra J, Delaney AD, Zhao Y, Siddiqui A, Asano J, McDonald H et al.. Large-scale production of SAGE libraries from microdissected tissues, flow-sorted cells, and cell lines. Genome Res. 2007; 17:108-16.
• [83]Lash AE, Tolstoshev CM, Wagner L, Schuler GD, Strausberg RL, Riggins GJ et al.. SAGEmap: a public gene expression resource. Genome Res. 2000; 10:1051-60.
• [84]Siddiqui AS, Khattra J, Delaney AD, Zhao Y, Astell C, Asano J et al.. A mouse atlas of gene expression: large-scale digital gene-expression profiles from precisely defined developing C57BL/6 J mouse tissues and cells. Proc Natl Acad Sci U S A. 2005; 102:18485-90.
• [85]Bailey TL, Boden M, Buske FA, Frith M, Grant CE, Clementi L et al.. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 2009; 37:W202-8.
• [86]Visel A, Thaller C, Eichele G. GenePaint.org: an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res. 2004; 32:D552-6.
• [87]Diez-Roux G, Banfi S, Sultan M, Geffers L, Anand S, Rozado D et al.. A high-resolution anatomical atlas of the transcriptome in the mouse embryo. PLoS Biol. 2011; 9:e1000582.
• [88]Singaraja RR, Huang K, Sanders SS, Milnerwood AJ, Hines R, Lerch JP et al.. Altered palmitoylation and neuropathological deficits in mice lacking HIP14. Hum Mol Genet. 2011; 20:3899-909.
• [89]Yang GS, Banks KG, Bonaguro RJ, Wilson G, Dreolini L, de Leeuw CN et al.. Next generation tools for high-throughput promoter and expression analysis employing single-copy knock-ins at the Hprt1 locus. Genomics. 2009; 93:196-204.