Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Dec:85:183-189.
doi: 10.1016/j.mcn.2017.10.003. Epub 2017 Oct 18.

Cocaine alters Homer1 natural antisense transcript in the nucleus accumbens

Gregory C Sartor  1 , Samuel K Powell  1 , Dmitry Velmeshev  1 , David Y Lin  1 , Marco Magistri  1 , Hannah J Wiedner  1 , Andrea M Malvezzi  1 , Nadja S Andrade  1 , Mohammad A Faghihi  1 , Claes Wahlestedt  2
Affiliations

Cocaine alters Homer1 natural antisense transcript in the nucleus accumbens

Gregory C Sartor et al. Mol Cell Neurosci. 2017 Dec.

Abstract

Natural antisense transcripts (NATs) are an abundant class of long noncoding RNAs that have recently been shown to be key regulators of chromatin dynamics and gene expression in nervous system development and neurological disorders. However, it is currently unclear if NAT-based mechanisms also play a role in drug-induced neuroadaptations. Aberrant regulation of gene expression is one critical factor underlying the long-lasting behavioral abnormalities that characterize substance use disorder, and it is possible that some drug-induced transcriptional responses are mediated, in part, by perturbations in NAT activity. To test this hypothesis, we used an automated algorithm that mines the NCBI AceView transcriptomics database to identify NAT overlapping genes linked to addiction. We found that 22% of the genes examined contain NATs and that expression of Homer1 natural antisense transcript (Homer1-AS) was altered in the nucleus accumbens (NAc) of mice 2h and 10days following repeated cocaine administration. In in vitro studies, depletion of Homer1-AS lead to an increase in the corresponding sense gene expression, indicating a potential regulatory mechanisms of Homer1 expression by its corresponding antisense transcript. Future in vivo studies are needed to definitely determine a role for Homer1-AS in cocaine-induced behavioral and molecular adaptations.

Keywords: Cocaine; Epigenetics; Long noncoding RNA; Natural antisense transcripts; Nucleus accumbens.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Bioinformatics pipeline and classification of noncoding antisense RNAs
(A) Schematic of bioinformatics pipeline used to identify natural antisense transcripts. (B) One hundred and twenty-one noncoding antisense (AS) RNAs were identified from 545 genes examined. (C) Gene ontology analysis of NAT-containing genes based on protein class.
Figure 2
Figure 2. Expression of noncoding antisense RNAs in the NAc
Following repeated cocaine or saline injections, NAc was collected for qPCR analysis. Significant change in Homer1-AS expression was revealed in cocaine-treated mice. *P < 0.0001 compared to saline via Benjamini and Hochberg false discovery rate test, n = 7–9.
Figure 3
Figure 3. Homer1 and Homer1-AS expression following repeated or acute cocaine injections
Repeated cocaine injections increased Homer1-AS, but not Homer1, in the NAc 2 hours (A) and 10 days (B) after the last injection. C) Increased Homer1, but not Homer1-AS, expression in the NAc 2 hours following a single injection of cocaine. *P < 0.005 and **P < 0.0005 compared to saline via Bonferroni post-hoc test, n = 6–9.
Figure 4
Figure 4. Graphical representation of Homer1 sense and antisense map
Genomic location of mouse antisense (blue) and sense (green) RNA pairs for Homer1.
Figure 5
Figure 5. Sense and antisense expression following Homer1-AS knockdown
A) Reduction of Homer1-AS following siRNA treatment in N2a cells. B) Increase in Homer1 expression following Homer1-AS knockdown in N2a cells. *P < 0.05, **P < 0.01, ***P < 0.0001 compared to si-Control via Newman-Keuls post-hoc test.
See this image and copyright information in PMC

References

    1. Bali P, Kenny PJ. MicroRNAs and Drug Addiction. Front Genet. 2013;4:43. - PMC - PubMed
    1. Bannon MJ, Savonen CL, Jia H, Dachet F, Halter SD, Schmidt CJ, Lipovich L, Kapatos G. Identification of long noncoding RNAs dysregulated in the midbrain of human cocaine abusers. J Neurochem. 2015;135:50–59. - PMC - PubMed
    1. Belgard TG, Marques AC, Oliver PL, Abaan HO, Sirey TM, Hoerder-Suabedissen A, Garcia-Moreno F, Molnar Z, Margulies EH, Ponting CP. A transcriptomic atlas of mouse neocortical layers. Neuron. 2011;71:605–616. - PMC - PubMed
    1. Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, Kuehn MS, Taylor CM, Neph S, Koch CM, Asthana S, Malhotra A, Adzhubei I, Greenbaum JA, Andrews RM, Flicek P, Boyle PJ, Cao H, Carter NP, Clelland GK, Davis S, Day N, Dhami P, Dillon SC, Dorschner MO, Fiegler H, Giresi PG, Goldy J, Hawrylycz M, Haydock A, Humbert R, James KD, Johnson BE, Johnson EM, Frum TT, Rosenzweig ER, Karnani N, Lee K, Lefebvre GC, Navas PA, Neri F, Parker SC, Sabo PJ, Sandstrom R, Shafer A, Vetrie D, Weaver M, Wilcox S, Yu M, Collins FS, Dekker J, Lieb JD, Tullius TD, Crawford GE, Sunyaev S, Noble WS, Dunham I, Denoeud F, Reymond A, Kapranov P, Rozowsky J, Zheng D, Castelo R, Frankish A, Harrow J, Ghosh S, Sandelin A, Hofacker IL, Baertsch R, Keefe D, Dike S, Cheng J, Hirsch HA, Sekinger EA, Lagarde J, Abril JF, Shahab A, Flamm C, Fried C, Hackermuller J, Hertel J, Lindemeyer M, Missal K, Tanzer A, Washietl S, Korbel J, Emanuelsson O, Pedersen JS, Holroyd N, Taylor R, Swarbreck D, Matthews N, Dickson MC, Thomas DJ, Weirauch MT, Gilbert J, Drenkow J, Bell I, Zhao X, Srinivasan KG, Sung WK, Ooi HS, Chiu KP, Foissac S, Alioto T, Brent M, Pachter L, Tress ML, Valencia A, Choo SW, Choo CY, Ucla C, Manzano C, Wyss C, Cheung E, Clark TG, Brown JB, Ganesh M, Patel S, Tammana H, Chrast J, Henrichsen CN, Kai C, Kawai J, Nagalakshmi U, Wu J, Lian Z, Lian J, Newburger P, Zhang X, Bickel P, Mattick JS, Carninci P, Hayashizaki Y, Weissman S, Hubbard T, Myers RM, Rogers J, Stadler PF, Lowe TM, Wei CL, Ruan Y, Struhl K, Gerstein M, Antonarakis SE, Fu Y, Green ED, Karaoz U, Siepel A, Taylor J, Liefer LA, Wetterstrand KA, Good PJ, Feingold EA, Guyer MS, Cooper GM, Asimenos G, Dewey CN, Hou M, Nikolaev S, Montoya-Burgos JI, Loytynoja A, Whelan S, Pardi F, Massingham T, Huang H, Zhang NR, Holmes I, Mullikin JC, Ureta-Vidal A, Paten B, Seringhaus M, Church D, Rosenbloom K, Kent WJ, Stone EA, Batzoglou S, Goldman N, Hardison RC, Haussler D, Miller W, Sidow A, Trinklein ND, Zhang ZD, Barrera L, Stuart R, King DC, Ameur A, Enroth S, Bieda MC, Kim J, Bhinge AA, Jiang N, Liu J, Yao F, Vega VB, Lee CW, Ng P, Yang A, Moqtaderi Z, Zhu Z, Xu X, Squazzo S, Oberley MJ, Inman D, Singer MA, Richmond TA, Munn KJ, Rada-Iglesias A, Wallerman O, Komorowski J, Fowler JC, Couttet P, Bruce AW, Dovey OM, Ellis PD, Langford CF, Nix DA, Euskirchen G, Hartman S, Urban AE, Kraus P, Van Calcar S, Heintzman N, Kim TH, Wang K, Qu C, Hon G, Luna R, Glass CK, Rosenfeld MG, Aldred SF, Cooper SJ, Halees A, Lin JM, Shulha HP, Xu M, Haidar JN, Yu Y, Iyer VR, Green RD, Wadelius C, Farnham PJ, Ren B, Harte RA, Hinrichs AS, Trumbower H, Clawson H, Hillman-Jackson J, Zweig AS, Smith K, Thakkapallayil A, Barber G, Kuhn RM, Karolchik D, Armengol L, Bird CP, de Bakker PI, Kern AD, Lopez-Bigas N, Martin JD, Stranger BE, Woodroffe A, Davydov E, Dimas A, Eyras E, Hallgrimsdottir IB, Huppert J, Zody MC, Abecasis GR, Estivill X, Bouffard GG, Guan X, Hansen NF, Idol JR, Maduro VV, Maskeri B, McDowell JC, Park M, Thomas PJ, Young AC, Blakesley RW, Muzny DM, Sodergren E, Wheeler DA, Worley KC, Jiang H, Weinstock GM, Gibbs RA, Graves T, Fulton R, Mardis ER, Wilson RK, Clamp M, Cuff J, Gnerre S, Jaffe DB, Chang JL, Lindblad-Toh K, Lander ES, Koriabine M, Nefedov M, Osoegawa K, Yoshinaga Y, Zhu B, de Jong PJ. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007;447:799–816. - PMC - PubMed
    1. Brakeman PR, Lanahan AA, O’Brien R, Roche K, Barnes CA, Huganir RL, Worley PF. Homer: a protein that selectively binds metabotropic glutamate receptors. Nature. 1997;386:284–288. - PubMed

Publication types

MeSH terms