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• W2010238834 abstract "The pineal gland plays an essential role in vertebrate chronobiology by converting time into a hormonal signal, melatonin, which is always elevated at night. Here we have analyzed the rodent pineal transcriptome using Affymetrix GeneChip® technology to obtain a more complete description of pineal cell biology. The effort revealed that 604 genes (1,268 probe sets) with Entrez Gene identifiers are differentially expressed greater than 2-fold between midnight and mid-day (false discovery rate <0.20). Expression is greater at night in ∼70%. These findings were supported by the results of radiochemical in situ hybridization histology and quantitative real time-PCR studies. We also found that the regulatory mechanism controlling the night/day changes in the expression of most genes involves norepinephrine-cyclic AMP signaling. Comparison of the pineal gene expression profile with that in other tissues identified 334 genes (496 probe sets) that are expressed greater than 8-fold higher in the pineal gland relative to other tissues. Of these genes, 17% are expressed at similar levels in the retina, consistent with a common evolutionary origin of these tissues. Functional categorization of the highly expressed and/or night/day differentially expressed genes identified clusters that are markers of specialized functions, including the immune/inflammation response, melatonin synthesis, photodetection, thyroid hormone signaling, and diverse aspects of cellular signaling and cell biology. These studies produce a paradigm shift in our understanding of the 24-h dynamics of the pineal gland from one focused on melatonin synthesis to one including many cellular processes. The pineal gland plays an essential role in vertebrate chronobiology by converting time into a hormonal signal, melatonin, which is always elevated at night. Here we have analyzed the rodent pineal transcriptome using Affymetrix GeneChip® technology to obtain a more complete description of pineal cell biology. The effort revealed that 604 genes (1,268 probe sets) with Entrez Gene identifiers are differentially expressed greater than 2-fold between midnight and mid-day (false discovery rate <0.20). Expression is greater at night in ∼70%. These findings were supported by the results of radiochemical in situ hybridization histology and quantitative real time-PCR studies. We also found that the regulatory mechanism controlling the night/day changes in the expression of most genes involves norepinephrine-cyclic AMP signaling. Comparison of the pineal gene expression profile with that in other tissues identified 334 genes (496 probe sets) that are expressed greater than 8-fold higher in the pineal gland relative to other tissues. Of these genes, 17% are expressed at similar levels in the retina, consistent with a common evolutionary origin of these tissues. Functional categorization of the highly expressed and/or night/day differentially expressed genes identified clusters that are markers of specialized functions, including the immune/inflammation response, melatonin synthesis, photodetection, thyroid hormone signaling, and diverse aspects of cellular signaling and cell biology. These studies produce a paradigm shift in our understanding of the 24-h dynamics of the pineal gland from one focused on melatonin synthesis to one including many cellular processes. A defining feature of the pineal gland is a 24-h rhythm in melatonin synthesis. Melatonin provides vertebrates with a circulating signal of time and is essential for optimal integration of physiological functions with environmental lighting on a daily and seasonal basis (1Maronde E. Stehle J.H. Trends Endocrinol. Metab. 2007; 18: 142-149Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 2Arendt J. Melatonin and the Mammalian Pineal Gland.1st Ed. Chapman & Hall, New York1994: 1-331Google Scholar, 3Lincoln G.A. Chronobiol. Int. 2006; 23: 301-306Crossref PubMed Scopus (39) Google Scholar, 4Klein D.C. CIBA Found. Symp. 1985; 117: 38-56PubMed Google Scholar). The melatonin rhythm in mammals is driven by a circadian clock located in the suprachiasmatic nucleus (SCN), 13The abbreviations used are: SCN, suprachiasmatic nucleus; Bt2cAMP, dibutyryl cAMP; CREB, cAMP-response element-binding protein; pCREB, phosphor-CREB; CRE, cAMP response element; cGMP, cyclic guanosine monophosphate; FDR, false discovery rate; qRT-PCR, quantitative real time-PCR; PWM, position weight matrices; SCG, superior cervical ganglia; NE, norepinephrine; ZT, Zeitgeber time; LD, light-dark; T3, thyroid hormone. which is hard-wired to the pineal gland by a polysynaptic pathway that courses through central and peripheral neuronal structures. The pineal gland is innervated by projections from the superior cervical ganglia (SCG) in the form of a dense network of catecholamine-containing sympathetic fibers. Activation of the SCN → pineal pathway occurs at night and results in the release of norepinephrine (NE) from the sympathetic fibers into the pineal perivascular space (5Moller M. Baeres F.M. Cell Tissue Res. 2002; 309: 139-150Crossref PubMed Scopus (171) Google Scholar). NE activates the pinealocyte through adrenergic receptors (5Moller M. Baeres F.M. Cell Tissue Res. 2002; 309: 139-150Crossref PubMed Scopus (171) Google Scholar, 6Klein D.C. Sugden D. Weller J.L. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 599-603Crossref PubMed Google Scholar). The best studied mechanism involves coincident “AND” gate activation of α1b- and β1-adrenergic receptors, which maximally stimulates adenylate cyclase, thereby elevating cAMP (7Sugden L.A. Sugden D. Klein D.C. J. Biol. Chem. 1987; 262: 741-745Abstract Full Text PDF PubMed Google Scholar, 8Auerbach D.A. Klein D.C. Woodard C. Aurbach G.D. Endocrinology. 1981; 108: 559-567Crossref PubMed Scopus (39) Google Scholar, 9Chik C.L. Ho A.K. Klein D.C. Endocrinology. 1988; 122: 702-708Crossref PubMed Google Scholar, 10Sugden D. Klein D.C. Endocrinology. 1984; 114: 435-440Crossref PubMed Google Scholar, 11Sugden A.L. Sugden D. Klein D.C. J. Biol. Chem. 1986; 261: 11608-11612Abstract Full Text PDF PubMed Google Scholar, 12Sugden D. Anwar N. Klein D.C. Br. J. Pharmacol. 1996; 118: 1246-1252Crossref PubMed Scopus (12) Google Scholar, 13Vanecek J. Sugden D. Weller J. Klein D.C. Endocrinology. 1985; 116: 2167-2173Crossref PubMed Google Scholar). Activation of α1b-adrenergic receptors alone elevates intracellular calcium and phospholipid signaling (1Maronde E. Stehle J.H. Trends Endocrinol. Metab. 2007; 18: 142-149Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 14Ho A.K. Klein D.C. J. Biol. Chem. 1987; 262: 11764-11770Abstract Full Text PDF PubMed Google Scholar, 15Ho A.K. Klein D.C. J. Neurochem. 1987; 48: 1033-1038Crossref PubMed Scopus (16) Google Scholar, 16Ho A.K. Chik C.L. Klein D.C. J. Pineal Res. 1988; 5: 553-564Crossref PubMed Scopus (24) Google Scholar). cAMP is believed to mediate the effects of NE on melatonin production to a large part by activating cAMP-dependent protein kinase. In rodents, this induces expression of Aanat, the penultimate enzyme in melatonin synthesis (17Klein D.C. J. Biol. Chem. 2007; 282: 4233-4237Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar). Induction occurs through phosphorylation of cAMP-response element-binding protein (CREB) bound to cAMP-response elements (CREs) in the Aanat gene. A similar NE/cAMP mechanism also controls expression of Adra1b, Atp7b, Crem, 14One transcript isoform of Crem, termed Icer, is known to be highly rhythmic in the rat pineal gland. Therefore, throughout the text, when Crem is mentioned in the context of the pineal gland, the term refers to the Icer isoform. Dio2, Fosl2, Id1, Dusp1, Mat2a, Nr4a1, Slc15a1, Pde4b2, Ptch1, and Rorb (18Baler R. Coon S.L. Klein D.C. Biochem. Biophys. Res. Commun. 1996; 220: 975-978Crossref PubMed Scopus (38) Google Scholar, 19Coon S.L. McCune S.K. Sugden D. Klein D.C. Mol. Pharmacol. 1997; 51: 551-557Crossref PubMed Scopus (31) Google Scholar, 20Li X. Chen S. Wang Q. Zack D.J. Snyder S.H. Borjigin J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 1876-1881Crossref PubMed Scopus (101) Google Scholar, 21Borjigin J. Payne A.S. Deng J. Li X. Wang M.M. Ovodenko B. Gitlin J.D. Snyder S.H. J. Neurosci. 1999; 19: 1018-1026Crossref PubMed Google Scholar, 22Kim J.S. Bailey M.J. Ho A.K. Moller M. Gaildrat P. Klein D.C. Endocrinology. 2007; 148: 1475-1485Crossref PubMed Scopus (29) Google Scholar, 23Gaildrat P. Moller M. Mukda S. Humphries A. Carter D.A. Ganapathy V. Klein D.C. J. Biol. Chem. 2005; 280: 16851-16860Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 24Stehle J.H. Foulkes N.S. Molina C.A. Simonneaux V. Pevet P. Sassone-Corsi P. Nature. 1993; 365: 314-320Crossref PubMed Scopus (346) Google Scholar, 25Baler R. Klein D.C. J. Biol. Chem. 1995; 270: 27319-27325Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 26Humphries A. Klein D. Baler R. Carter D.A. J. Neuroendocrinol. 2002; 14: 101-108Crossref PubMed Scopus (49) Google Scholar, 27Borjigin J. Deng J. Wang M.M. Li X. Blackshaw S. Snyder S.H. J. Biol. Chem. 1999; 274: 35012-35015Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). In addition, a NE/cAMP mechanism decreases expression of Hs3st2 (28Borjigin J. Deng J. Sun X. De Jesus M. Liu T. Wang M.M. J. Biol. Chem. 2003; 278: 16315-16319Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Although it is likely that some of the effects of cAMP involve CREs, it is also likely that cAMP influences pineal gene expression through epigenetic mechanisms that alter chromatin structure, e.g. histone phosphorylation (29Chik C.L. Arnason T.G. Dukewich W.G. Price D.M. Ranger A. Ho A.K. Endocrinology. 2007; 148: 1465-1472Crossref PubMed Scopus (12) Google Scholar, 30Ho A.K. Price D.M. Dukewich W.G. Steinberg N. Arnason T.G. Chik C.L. Endocrinology. 2007; 148: 4592-4600Crossref PubMed Scopus (14) Google Scholar), thereby having the potential of altering the expression of many genes and broadly promoting transcription by factors other than CREB. Whereas there is abundant evidence that the SCN/SCG/NE/cAMP system controls rhythmic gene expression in the pineal gland, it is also possible that other regulatory mechanisms exist, involving release of other transmitters, and additional second messengers (e.g. cGMP, Ca2+, and phospholipids). The increased abundance of some of these night/day differentially expressed genes and of other genes in the pineal gland is determined in part by members of the OTX2/CRX family of homeodomain proteins, which play a similar role in the retina (31Furukawa A. Koike C. Lippincott P. Cepko C.L. Furukawa T. J. Neurosci. 2002; 22: 1640-1647Crossref PubMed Google Scholar, 32Furukawa T. Morrow E.M. Li T. Davis F.C. Cepko C.L. Nat. Genet. 1999; 23: 466-470Crossref PubMed Scopus (420) Google Scholar, 33Appelbaum L. Gothilf Y. Mol. Cell. Endocrinol. 2006; 252: 27-33Crossref PubMed Scopus (30) Google Scholar, 34Rath M.F. Munoz E. Ganguly S. Morin F. Shi Q. Klein D.C. Moller M. J. Neurochem. 2006; 97: 556-566Crossref PubMed Scopus (49) Google Scholar). These factors bind to photoreceptor conserved elements and closely related sequences. In addition, Pax6 and Otx2 are essential for development of both tissues (35Estivill-Torrus G. Vitalis T. Fernandez-Llebrez P. Price D.J. Mech. Dev. 2001; 109: 215-224Crossref PubMed Scopus (88) Google Scholar, 36Gehring W.J. Int. J. Dev. Biol. 2002; 46: 65-73PubMed Google Scholar, 37Nishida A. Furukawa A. Koike C. Tano Y. Aizawa S. Matsuo I. Furukawa T. Nat. Neurosci. 2003; 6: 1255-1263Crossref PubMed Scopus (400) Google Scholar). This developmental similarity is consistent with the common evolutionary origin of the pineal gland and retina from a primitive photodetector (38Klein D.C. Chronobiol. Int. 2006; 23: 5-20Crossref PubMed Scopus (62) Google Scholar). Examples of OTX2/CRX-controlled genes expressed in both tissues include Aanat, Asmt, Sag, and Grk1 (20Li X. Chen S. Wang Q. Zack D.J. Snyder S.H. Borjigin J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 1876-1881Crossref PubMed Scopus (101) Google Scholar, 39Dinet V. Girard-Naud N. Voisin P. Bernard M. Exp. Eye Res. 2006; 83: 276-290Crossref PubMed Scopus (12) Google Scholar, 40Kimura A. Singh D. Wawrousek E.F. Kikuchi M. Nakamura M. Shinohara T. J. Biol. Chem. 2000; 275: 1152-1160Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 41Appelbaum L. Anzulovich A. Baler R. Gothilf Y. J. Biol. Chem. 2005; 280: 11544-11551Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 42Appelbaum L. Toyama R. Dawid I.B. Klein D.C. Baler R. Gothilf Y. Mol. Endocrinol. 2004; 18: 1210-1221Crossref PubMed Scopus (43) Google Scholar, 43Bernard M. Dinet V. Voisin P. J. Neurochem. 2001; 79: 248-257Crossref PubMed Scopus (25) Google Scholar, 44Gothilf Y. Toyama R. Coon S.L. Du S.J. Dawid I.B. Klein D.C. Dev. Dyn. 2002; 225: 241-249Crossref PubMed Scopus (39) Google Scholar, 45Mani S.S. Besharse J.C. Knox B.E. J. Biol. Chem. 1999; 274: 15590-15597Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 46Young J.E. Kasperek E.M. Vogt T.M. Lis A. Khani S.C. Genomics. 2007; 90: 236-248Crossref PubMed Scopus (4) Google Scholar). The first two encode proteins dedicated to melatonin synthesis; the latter two encode proteins associated with phototransduction in the retina. It is not clear whether the proteins encoded by these phototransduction genes play parallel roles in NE/cAMP signal transduction in the pinealocyte or if they are functionally vestigial in the context of the pinealocyte. Although OTX2 and CRX are of central importance in these tissues, it appears that other transcription factors and regulatory cascades are involved. For example, the importance of E-boxes in determining tissue-specific expression of Aanat is evident from several studies (42Appelbaum L. Toyama R. Dawid I.B. Klein D.C. Baler R. Gothilf Y. Mol. Endocrinol. 2004; 18: 1210-1221Crossref PubMed Scopus (43) Google Scholar, 47Gothilf Y. Coon S.L. Toyama R. Chitnis A. Namboodiri M.A. Klein D.C. Endocrinology. 1999; 140: 4895-4903Crossref PubMed Scopus (120) Google Scholar), and NeuroD1 may also play a role in determining pineal gland-specific expression patterns (48Munoz E.M. Bailey M.J. Rath M.F. Shi Q. Morin F. Coon S.L. Moller M. Klein D.C. J. Neurochem. 2007; 102: 887-899Crossref PubMed Scopus (31) Google Scholar). Whereas in both the pineal gland and retina, photoreceptor conserved elements control developmental expression of the same gene, different mechanisms can operate in each tissue to control rhythmicity. For example, in the case of Aanat, CREs mediate cAMP control of 24-h rhythms in the pineal gland (49Roseboom P.H. Klein D.C. Mol. Pharmacol. 1995; 47: 439-449PubMed Google Scholar, 50Baler R. Covington S. Klein D.C. J. Biol. Chem. 1997; 272: 6979-6985Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). In the retina, however, E-box elements mediate circadian clock control of the 24-h rhythm in Aanat expression (51Tosini G. Chaurasia S.S. Michael Iuvone P. Chronobiol. Int. 2006; 23: 381-391Crossref PubMed Scopus (31) Google Scholar). In addition to the accepted SCN/SCG/NE/cAMP pathway, reports in the literature have claimed that a circadian clock regulates daily changes in the expression of some genes in the mammalian pineal gland (52Fukuhara C. Liu C. Ivanova T.N. Chan G.C. Storm D.R. Iuvone P.M. Tosini G. J. Neurosci. 2004; 24: 1803-1811Crossref PubMed Scopus (95) Google Scholar), as in the submammalian pineal gland (53Iuvone P.M. Bernard M. Alonso-Gomez A. Greve P. Cassone V.M. Klein D.C. Biol. Signals. 1997; 6: 217-224Crossref PubMed Scopus (26) Google Scholar, 54Falcon J. Gothilf Y. Coon S.L. Boeuf G. Klein D.C. J. Neuroendocrinol. 2003; 15: 378-382Crossref PubMed Scopus (78) Google Scholar). The physiological impact of this remains unknown. Here we have expanded our understanding of the transcriptional regulation and physiology of the pineal gland by employing Affymetrix GeneChip® technology, including a microarray that interrogates more than 13,663 genes that have been assigned Entrez Gene identifiers. 15Where numbers of genes in various categories are given, this refers to probe sets that have been annotated with Entrez Gene identifiers by Affymetrix as of November 5, 2007, and updated manually as of June 15, 2008. The gene symbols that are used have been taken from Entrez Gene; associated Gene titles and Entrez Gene identifiers are given in supplemental Tables S3, S4, and S5. Gene symbols beginning with LOC, RGD, or MGC are not included in the tables in the text; they are included in the supplemental tables. Previous studies of this nature in the rat have identified 39 night/day differentially expressed genes (26Humphries A. Klein D. Baler R. Carter D.A. J. Neuroendocrinol. 2002; 14: 101-108Crossref PubMed Scopus (49) Google Scholar); a more recent study identified 35 such genes with Entrez Gene identifiers (59 probe sets) (55Fukuhara C. Tosini G. Neurosci. Res. 2008; 60: 192-198Crossref PubMed Scopus (18) Google Scholar). Our study had three specific goals. The first goal was to produce a comprehensive listing of genes that are differentially expressed on a night/day basis. The second goal was to identify the highly enriched genes that define pineal function, independent of whether they are tonically or night/day differentially expressed; this was done by comparing gene expression in the pineal gland to median expression among other tissues. The third goal was to determine the scope of the NE/cAMP regulatory cascade; this approach utilized an in vitro organ culture system. In addition to establishing the importance of this cascade, the organ culture studies identified sets of genes that were spontaneously up- or down-regulated more than 10-fold during culture in defined medium, providing evidence of the existence of unknown regulatory mechanisms. An unexpected discovery was that the pineal transcriptome includes a large number of immune/inflammation response-associated genes. The findings of this study are of value to investigators interested in the pineal gland, chronobiology, neuroendocrinology, and immunology and to those who study specific genes that are night/day differentially and/or highly expressed in the pineal gland. Three microarray experiments were done (experiments A, B, and C). For microarray experiments A and B (Cardiff University), Sprague-Dawley rats (2–3 months old) were maintained in standard laboratory conditions in a 14:10 light-dark (LD) cycle (lights on, 05:00 h). Animals were killed at mid-day (ZT7) or midnight (ZT19) by cervical dislocation, and pineal glands were rapidly dissected, placed in tubes on solid CO2, and stored at –80 °C. For microarray experiment C (NICHD, National Institutes of Health), for the time series analysis of gene expression by qRT-PCR (Fig. 4), and for organ culture experiments, Sprague-Dawley rats (2–3 months old, female) were housed for 2 weeks in LD 14:10 lighting cycles, killed by CO2 asphyxiation, and decapitated; pineal glands were rapidly dissected and either placed in tubes on solid CO2 and stored at –80 °C or were prepared for organ culture. Other tissues were also removed, and 10-mg samples were frozen and stored in a similar manner. For the qRT-PCR experiment (Fig. 4), tissues were collected at ZT1, -7, -13.5, -15, -16, -17.5, -19, and -22, placed in tubes on solid CO2, and stored at –80 °C. Glands for organ culture experiments were obtained at ZT4–6 and placed in culture within 60 min. For radiochemical in situ hybridization histology studies (University of Copenhagen), Sprague-Dawley and Wistar rats (Charles River, Germany) were housed for 2 weeks in a controlled lighting environment (LD 12:12). Animals were killed by decapitation at ZT6 and ZT18; their brains were removed, immediately placed in solid CO2, and stored at –80 °C until sectioned. Animal use and care protocols were approved by local ethical review, and they were in accordance with National Institutes of Health guidelines, United Kingdom Home Office Regulations, and Health Sciences Animal Policy European Union Directive 86/609/EEC (approved by the Danish Council for Animal Experiments). For organ culture, rat pineal glands were cultured in BGJb medium as described previously (56Parfitt A. Weller J.L. Klein D.C. Neuropharmacology. 1976; 15: 353-358Crossref PubMed Scopus (107) Google Scholar) and detailed in the supplemental material. Glands were incubated (1 gland/well) with fresh media containing NE (1 μm), dibutyryl cAMP (Bt2cAMP; 0.5 or 1 mm), or forskolin (10 μm) (Sigma). Following a 6-h treatment, glands were placed in microtubes on solid CO2. To confirm that the glands were activated by the drugs, melatonin production in the culture media was measured by tandem mass spectroscopy as described (57Yu A.M. Idle J.R. Byrd L.G. Krausz K.W. Kupfer A. Gonzalez F.J. Pharmacogenetics. 2003; 13: 173-181Crossref PubMed Scopus (155) Google Scholar), with an internal d4-melatonin standard. The amount of melatonin produced (nanomoles/gland/6 h; means ± S.E.) for the control, NE-treated, Bt2cAMP-treated, and forskolin-treated groups was (number of samples) 1.4 ± 0.1 (9Chik C.L. Ho A.K. Klein D.C. Endocrinology. 1988; 122: 702-708Crossref PubMed Google Scholar); 20.3 ± 1.1 (9Chik C.L. Ho A.K. Klein D.C. Endocrinology. 1988; 122: 702-708Crossref PubMed Google Scholar); 9.9 ± 0.9 (9Chik C.L. Ho A.K. Klein D.C. Endocrinology. 1988; 122: 702-708Crossref PubMed Google Scholar); and 15.0 ± 1.2 (9Chik C.L. Ho A.K. Klein D.C. Endocrinology. 1988; 122: 702-708Crossref PubMed Google Scholar), respectively. For the analysis of pineal glands in experiments A and B, two sets of six pooled samples of four rat pineal glands each were prepared (three night and three day). In experiment C, four pools, each containing three glands, were prepared for each time point; as part of this experiment, single retinas and 10-mg samples of the cerebellum, neocortex, hypothalamus, liver, and heart were also obtained. Glands were also obtained from organ culture experiments in which each treatment group was comprised of three pools, each containing four glands. Total RNA was isolated, labeled and used to interrogate Affymetrix GeneChips® as detailed in the supplemental material. The microarray data presented here are derived from the experiments described below (A, B, and C) in conjunction with a published tissue profiling effort (Genomics Institute of the Novartis Research Foundation (GNF), Entrez Gene Expression Omnibus (GEO), dataset GDS589 (58Walker J.R. Su A.I. Self D.W. Hogenesch J.B. Lapp H. Maier R. Hoyer D. Bilbe G. Genome Res. 2004; 14: 742-749Crossref PubMed Scopus (73) Google Scholar)). Microarray experiment A (Cardiff University) used the Affymetrix RG_U34A microarray (8,799 probe sets, 4,996 genes). Results from microarray experiment A were compared with data from the GNF data base, which had been generated using the same microarray. Expression data for the following 23 Sprague-Dawley tissues and isolated cells were used (number of samples per tissue is in parentheses): neocortex (39), cerebellum (17), striatum (13), hippocampus (3), hypothalamus (2), pituitary (2), amygdala (10), nucleus accumbens (6), locus ceruleus (2), dorsal raphe (2), ventral tegmental area (2), pineal gland (2), dorsal root ganglion (2), cornea (2), heart (2), intestine (4), kidney (2), spleen (2), thymus (2), bone marrow (2), muscle (2), Sertoli cells (10), and endothelial cells (2). Microarray experiment B (Cardiff University) used the RAE230A microarray (15,923 probe sets, 10,174 genes). Microarray experiment C (NICHD, National Institutes of Health) used the Rat230_2 microarray (31,099 probe sets, 13,663 genes); this experiment included pineal glands and other tissues (retina, neocortex, cerebellum, hypothalamus, heart, and liver) obtained at mid-day and midnight, and glands obtained from organ culture. Night/Day Differences in Gene Expression-Affymetrix MAS5 Signal and Present Call values were stored in the NIH-LIMS, a data base for storage and retrieval of microarray data. The microarray data are available at the Entrez Gene Expression Omnibus, National Center for Biotechnology Information (59Edgar R. Domrachev M. Lash A.E. Nucleic Acids Res. 2002; 30: 207-210Crossref PubMed Google Scholar), and are accessible through GEO series accession number GSE12344 (ncbi.nlm.nih.gov), and at sne.nichd.nih.gov. Data were statistically analyzed using the MSCL Analyst Toolbox (P. J. Munson, J. J. Barb, abs.cit.nih.gov) and the JMP statistical software package (SAS, Inc., Cary, NC). Affymetrix signal values were incremented by a value of 0.1× microarray median value, then normalized to 1.1× microarray median values, and finally decimal log-transformed. This transformation is termed “Lmed” and has the desirable effect of reducing the influence of very small expression values. One-way, two-level analysis of variance testing differences between night and day were performed on the transformed data, and significance (p values, or false discovery rate (FDR) (60Benjamini Y. Hochberg Y. J. R. Stat. Soc. Ser. B. 1995; 57: 289-300Google Scholar)) was reported (see supplemental Table S3). Night-day log fold changes were computed as the difference between the night and day Lmed values; in experiment C, NE/control and Bt2cAMP/control log fold change values were calculated similarly. Expression ratios are reported as linear values; values less than one are reported using the 1/X convention in which X = the night/day ratio, i.e. a night/day ratio of 0.01 is displayed as 1/100. Table 1 details the expression ratios (night/day, NE/control, Bt2cAMP/control) of all genes with a Entrez Gene identifier and with a night/day ratio greater than 4 or less than ¼. The supplemental Table S3 presents the expression ratios of all probe sets with a night/day ratio greater than 2 or less than ½.TABLE 1Differential expression of genes in the pineal gland* Predicted gene is indicated. Open table in a new tab * Predicted gene is indicated. Expression of Genes in the Pineal Gland Relative to Other Tissues-Gene expression in one tissue relative to expression in other tissues was defined as the relative tissue expression (rEx) value, which was calculated as the ratio of maximum expression (the highest of day or night) to the median expression of that gene in other tissues. In experiment A, median values were calculated from 23 Sprague-Dawley tissues in the GNF data base (see above) plus the day and night pineal gland values generated in experiment A. In experiment C, the median values were calculated from the average expression levels in each of seven tissues (see above). These averages were based on single mid-day and midnight values, except in the case of the pineal gland for which four mid-day and four midnight values were used. The larger of two rEx values obtained using the two experiments is presented in Table 3, which contains genes with rEx values greater than 8. The supplemental Table S4 includes rEx values from both experiments for probe sets with rEx values greater than 2.TABLE 3Genes highly expressed in the pineal gland relative to other tissuesPineal rExGene symbol>16A2m, Aanat, Abca1, Abhd14b, Adra1b, Adrb1, Aipl1, Alox15, Arhgap24, Arr3, Asl, Asmt, Atp7b, Ca3, Cabp1, Cacna1f, Camk1g, Ccl9, Cd1d1, Cd24, Cdh22, Chga, Chrna3, Chrnb4, Cnga1, Cngb1, Cntrob,aPredicted gene is indicated. Col8a1,aPredicted gene is indicated. Cplx3, Cpt1b, Crem, Crocc,aPredicted gene is indicated. Crtac1, Crx, Ctsc, Cyp1b1, Dclk3,aPredicted gene is indicated. Ddc, Defb24, Drd4, Dusp1, Efemp1, Egflam, Esm1, Eya2, Fcer1a, Fdx1, Fkbp4, Fkbp5, Frmpd1,aPredicted gene is indicated. Fst, Fzd4, Gch, Gdf15, Gem,aPredicted gene is indicated. Gnat2,aPredicted gene is indicated. Gnb3, Grk1, Guca1a,aPredicted gene is indicated. Hs3st2, Hspa1a, Hspa1b, Hspb1, Igfbp6, Impg1, Impg2, Irak2, Irs1, Isl2, Ka15, Kcne2, Kcnh6, Kcnj14, Krt1-19, Lamp3, Lgals1, Lgals3, Lhx4,aPredicted gene is indicated. Lix1,aPredicted gene is indicated. Lpl, Lrrc21, M6prbp1, Map4k1,aPredicted gene is indicated. Mat2a, Mcam, Me2,aPredicted gene is indicated. Miox, Mitf, Morn1, Mpp3, Mpp4, Mtac2d1, Mx2, Ncaph, Neurod1, Nphp4, Nphs1, Nptx1, Opn1sw, Osap, Otx2, Padi4, Pax4, Pax6, Pcbd1, Pcdh21, Pdc, Pde4b, Pla2g5, Plscr1, Rbp3, Rds, Ribc2, Rom1, Rorb,aPredicted gene is indicated. Rxrg, Sag, Scn7a, Serping1, Slc12a5, Slc15a1, Slc17a6, Slc24a1, Slc30a1, Slc39a4,aPredicted gene is indicated. Slc6a6, Snap25, Snf1lk, Sorl1, Spink4, Stk22s1, Sv2b, Tm7sf2, Tph1, Ttr, Tulp1,aPredicted gene is indicated. Unc119, Vof168-16Accn4, Acsl1, Acvr1, Adam2, Ak3l1, Als2cr4,aPredicted gene is indicated. Ampd2, Anp32e, Anpep, Atp1b2, Atp6v1c2, Baiap2l1, Bmp6, Bzrp, Cacna1h, Ccdc125, Ccl2, Ccl6, Ccnd2, Cd63, Cd74, Cd8a, Cebpb, Cfd, Cflar, Chst2aPredicted gene is indicated. Cip98, Col15a1, Col1a1, Cr16, Crcp, Cyp1a1, Dcn, Depdc7, Dhrs8, Dnajc12, Dnm2, Dnm3, Dpt,aPredicted gene is indicated. Dsc2, Dscr1, Epb4.1, Errfi1, Etnk1,aPredicted gene is indicated. Exoc5, F5, Farp2,aPredicted gene is indicated. Fosl2, Foxd1, Frmd4b, G0s2, Gabrr1, Gale, Galnt4, Galntl1, Gla, Gls, Gmds, Gnas, Grm1, Hcn1, Hk2, Hsd3b7, Hspb6, Id1, Ifitm3, Igfbp2, Igsf1, Igsf4a, Il13ra2, Il17re, Irf7, Itgb2, Kctd14,aPredicted gene is indicated. Kctd3, Kit, Klhl4, Lad1,aPredicted gene is indicated. Lama2,aPredicted gene is indicated. Lamb1,aPredicted gene is indicated. Lmbr1l, Lmod1,aPredicted gene is indicated. Lnx1,aPredicted gene is indicated. Lox, Loxl1, Lrrc8e, Lum, Lxn, Mad2l2, Mak, Mak10, Man2a1, Mapk6, Msrb2, Msx1, Mt1a, Muc4, Mylk,aPredicted gene is indicated. Myo5b, Nacad, Nr4a1, Nradd, Nrap,aPredicted gene is indicated. Nup107, Oasl1, Orai1, Pcbp3, Pde10a, Pde6b,aPredicted gene is indicated. Pdp2, Pgam2, Pgm1, Pid1, P" @default.
• W2010238834 created "2016-06-24" @default.
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• W2010238834 creator A5085950606 @default.
• W2010238834 date "2009-03-01" @default.
• W2010238834 modified "2023-10-17" @default.
• W2010238834 title "Night/Day Changes in Pineal Expression of >600 Genes" @default.
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