Modular organization of a hypocretin gene minimal promoter

Sánchez‑García,Adriana; Cabral‑Pacheco,Griselda A.; Zomosa‑Signoret,Viviana C.; Ortiz‑López,Rocío; Camacho,Alberto; Tabera‑Tarello,Paulo M.; Garnica-López,José A.; Vidaltamayo,Román

doi:10.3892/mmr.2017.8142

Modular organization of a hypocretin gene minimal promoter

Authors:
- Adriana Sánchez‑García
- Griselda A. Cabral‑Pacheco
- Viviana C. Zomosa‑Signoret
- Rocío Ortiz‑López
- Alberto Camacho
- Paulo M. Tabera‑Tarello
- José A. Garnica-López
- Román Vidaltamayo
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Affiliations: Department of Biochemistry and Molecular Medicine, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, NL 64460, Mexico, Genomics Unit, Center for Research and Development in Health Sciences, Universidad Autonoma de Nuevo Leon, Monterrey, NL 64460, Mexico, Department of Basic Science, School of Health Sciences, Universidad de Monterrey, San Pedro Garzia, NL 66238, Mexico
Published online on: November 22, 2017 https://doi.org/10.3892/mmr.2017.8142
Pages: 2263-2270
Copyright: © Sánchez‑García et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Orexins or hypocretins are neurotransmitters produced by a small population of neurons in the lateral hypothalamus. This family of peptides modulates sleep‑wake cycle, arousal and feeding behaviors; however, the mechanisms regulating their expression remain to be fully elucidated. There is an interest in defining the key molecular elements in orexin regulation, as these may serve to identify targets for generating novel therapies for sleep disorders, obesity and addiction. Our previous studies showed that the expression of orexin was decreased in mice carrying null‑mutations of the transcription factor early B‑cell factor 2 (ebf2) and that the promoter region of the prepro‑orexin (Hcrt) gene contained two putative ebf‑binding sites, termed olf‑1 sites. In the present study, a minimal promoter region of the murine Hcrt gene was identified, which was able to drive the expression of a luciferase reporter gene in the human 293 cell line. Deletion of the olf1‑site proximal to the transcription start site of the Hcrt gene increased reporter gene expression, whereas deletion of the distal olf1‑like site decreased its expression. The lentiviral transduction of murine transcription factor ebf2 cDNA into 293 cells increased the gene expression driven by this minimal Hcrt‑gene promoter and an electrophoretic mobility shift assays demonstrated that the distal olf1‑like sequence was a binding site for ebf2.

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1	de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS II, et al: The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA. 95:pp. 322–327. 1998; View Article : Google Scholar : PubMed/NCBI
2	Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, et al: Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 92:573–585. 1998. View Article : Google Scholar : PubMed/NCBI
3	Routh VH, Hao L, Santiago AM, Sheng Z and Zhou C: Hypothalamic glucose sensing: Making ends meet. Front Syst Neurosci. 8:2362014. View Article : Google Scholar : PubMed/NCBI
4	Tsujino N and Sakurai T: Role of orexin in modulating arousal, feeding, and motivation. Front Behav Neurosci. 7:282013. View Article : Google Scholar : PubMed/NCBI
5	Nuñez A, Rodrigo-Angulo ML, Andrés ID and Garzón M: Hypocretin/orexin neuropeptides: Participation in the control of sleep-wakefulness cycle and energy homeostasis. Curr Neuropharmacol. 7:50–59. 2009. View Article : Google Scholar : PubMed/NCBI
6	Ohno K and Sakurai T: Orexin neuronal circuitry: Role in the regulation of sleep and wakefulness. Front Neuroendocrinol. 29:70–87. 2008. View Article : Google Scholar : PubMed/NCBI
7	Matsuki T and Sakurai T: Orexins and orexin receptors: From molecules to integrative physiology. Results Probl Cell Differ. 46:27–55. 2008. View Article : Google Scholar : PubMed/NCBI
8	Cai XJ, Widdowson PS, Harrold J, Wilson S, Buckingham RE, Arch JR, Tadayyon M, Clapham JC, Wilding J and Williams G: Hypothalamic orexin expression: Modulation by blood glucose and feeding. Diabetes. 48:2132–2137. 1999. View Article : Google Scholar : PubMed/NCBI
9	Griffond B, Risold PY, Jacquemard C, Colard C and Fellmann D: Insulin-induced hypoglycemia increases preprohypocretin (orexin) mRNA in the rat lateral hypothalamic area. Neurosci Lett. 262:77–80. 1999. View Article : Google Scholar : PubMed/NCBI
10	Wagner D, Salin-Pascual R, Greco MA and Shiromani PJ: Distribution of hypocretin-containing neurons in the lateral hypothalamus and C-fos-immunoreactive neurons in the VLPO. Sleep Res Online. 3:35–42. 2000.PubMed/NCBI
11	Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y, Kageyama H, Kunita S, Takahashi S, Goto K, et al: Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron. 46:297–308. 2005. View Article : Google Scholar : PubMed/NCBI
12	Tanaka S, Kodama T, Nonaka T, Toyoda H, Arai M, Fukazawa M, Honda Y, Honda M and Mignot E: Transcriptional regulation of the hypocretin/orexin gene by NR6A1. Biochem Biophys Res Commun. 403:178–183. 2010. View Article : Google Scholar : PubMed/NCBI
13	Sakurai T, Moriguchi T, Furuya K, Kajiwara N, Nakamura T, Yanagisawa M and Goto K: Structure and function of human prepro-orexin gene. J Biol Chem. 274:17771–17776. 1999. View Article : Google Scholar : PubMed/NCBI
14	Cunningham F, Amode MR, Barrell D, Beal K, Billis K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fitzgerald S, et al: Ensembl 2015. Nucleic Acids Res. 43(Database issue): D662–D669. 2015. View Article : Google Scholar : PubMed/NCBI
15	Waleh NS, Apte-Deshpande A, Terao A, Ding J and Kilduff TS: Modulation of the promoter region of prepro-hypocretin by alpha-interferon. Gene. 262:123–128. 2001. View Article : Google Scholar : PubMed/NCBI
16	Moriguchi T, Sakurai T, Takahashi S, Goto K and Yamamoto M: The human prepro-orexin gene regulatory region that activates gene expression in the lateral region and represses it in the medial regions of the hypothalamus. J Biol Chem. 277:16985–16992. 2002. View Article : Google Scholar : PubMed/NCBI
17	Tanaka S: Transcriptional regulation of the hypocretin/orexin gene. Vitam Horm. 89:75–90. 2012. View Article : Google Scholar : PubMed/NCBI
18	Honda M, Eriksson KS, Zhang S, Tanaka S, Lin L, Salehi A, Hesla PE, Maehlen J, Gaus SE, Yanagisawa M, et al: IGFBP3 colocalizes with and regulates hypocretin (orexin). PLoS One. 4:e42542009. View Article : Google Scholar : PubMed/NCBI
19	Silva JP, von Meyenn F, Howell J, Thorens B, Wolfrum C and Stoffel M: Regulation of adaptive behaviour during fasting by hypothalamic Foxa2. Nature. 462:646–650. 2009. View Article : Google Scholar : PubMed/NCBI
20	De La Herrán-Arita AK, Zomosa-Signoret VC, Millán-Aldaco DA, Palomero-Rivero M, Guerra-Crespo M, Drucker-Colín R and Vidaltamayo R: Aspects of the narcolepsy-cataplexy syndrome in O/E3-null mutant mice. Neuroscience. 183:134–143. 2011. View Article : Google Scholar : PubMed/NCBI
21	Wang SS, Lewcock JW, Feinstein P, Mombaerts P and Reed RR: Genetic disruptions of O/E2 and O/E3 genes reveal involvement in olfactory receptor neuron projection. Development. 131:1377–1388. 2004. View Article : Google Scholar : PubMed/NCBI
22	Garcia-Dominguez M, Poquet C, Garel S and Charnay P: Ebf gene function is required for coupling neuronal differentiation and cell cycle exit. Development. 130:6013–6025. 2003. View Article : Google Scholar : PubMed/NCBI
23	Croci L, Chung SH, Masserdotti G, Gianola S, Bizzoca A, Gennarini G, Corradi A, Rossi F, Hawkes R and Consalez GG: A key role for the HLH transcription factor EBF2COE2,O/E-3 in Purkinje neuron migration and cerebellar cortical topography. Development. 133:2719–2729. 2006. View Article : Google Scholar : PubMed/NCBI
24	Chuang SM, Wang Y, Wang Q, Liu KM and Shen Q: Ebf2 marks early cortical neurogenesis and regulates the generation of cajal-retzius neurons in the developing cerebral cortex. Dev Neurosci. 33:479–493. 2011. View Article : Google Scholar : PubMed/NCBI
25	Roby YA, Bushey MA, Cheng LE, Kulaga HM, Lee SJ and Reed RR: Zfp423/OAZ mutation reveals the importance of Olf/EBF transcription activity in olfactory neuronal maturation. J Neurosci. 32:13679–13688. 2012. View Article : Google Scholar : PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
27	Burt J, Alberto CO, Parsons MP and Hirasawa M: Local network regulation of orexin neurons in the lateral hypothalamus. Am J Physiol Regul Integr Comp Physiol. 301:R572–R580. 2011. View Article : Google Scholar : PubMed/NCBI
28	Tanno S, Terao A, Okamatsu-Ogura Y and Kimura K: Hypothalamic prepro-orexin mRNA level is inversely correlated to the non-rapid eye movement sleep level in high-fat diet-induced obese mice. Obes Res Clin Pract. 7:e251–e257. 2013. View Article : Google Scholar : PubMed/NCBI
29	Arafat AM, Kaczmarek P, Skrzypski M, Pruszyńska-Oszmałek E, Kołodziejski P, Adamidou A, Ruhla S, Szczepankiewicz D, Sassek M, Billert M, et al: Glucagon regulates orexin A secretion in humans and rodents. Diabetologia. 57:2108–2116. 2014. View Article : Google Scholar : PubMed/NCBI
30	Iwasa T, Matsuzaki T, Munkhzaya M, Tungalagsuvd A, Kuwahara A, Yasui T and Irahara M: Developmental changes in the hypothalamic mRNA levels of prepro-orexin and orexin receptors and their sensitivity to fasting in male and female rats. Int J Dev Neurosci. 46:51–54. 2015. View Article : Google Scholar : PubMed/NCBI
31	Justinussen JL, Holm A and Kornum BR: An optimized method for measuring hypocretin-1 peptide in the mouse brain reveals differential circadian regulation of hypocretin-1 levels rostral and caudal to the hypothalamus. Neuroscience. 310:354–361. 2015. View Article : Google Scholar : PubMed/NCBI
32	Zhou Y, Leri F, Cummins E and Kreek MJ: Individual differences in gene expression of vasopressin, D2 receptor, POMC and orexin: Vulnerability to relapse to heroin-seeking in rats. Physiol Behav. 139:127–135. 2015. View Article : Google Scholar : PubMed/NCBI
33	Dalal J, Roh JH, Maloney SE, Akuffo A, Shah S, Yuan H, Wamsley B, Jones WB, de Guzman Strong C, Gray PA, et al: Translational profiling of hypocretin neurons identifies candidate molecules for sleep regulation. Genes Dev. 27:565–578. 2013. View Article : Google Scholar : PubMed/NCBI
34	Liu J, Merkle FT, Gandhi AV, Gagnon JA, Woods IG, Chiu CN, Shimogori T, Schier AF and Prober DA: Evolutionarily conserved regulation of hypocretin neuron specification by Lhx9. Development. 142:1113–1124. 2015. View Article : Google Scholar : PubMed/NCBI
35	Szabó NE, Zhao T, Cankaya M, Theil T, Zhou X and Alvarez-Bolado G: Role of neuroepithelial Sonic hedgehog in hypothalamic patterning. J Neurosci. 29:6989–7002. 2009. View Article : Google Scholar : PubMed/NCBI