Characterization of a REST-Regulated Internal Promoter in the Schizophrenia Genome-Wide Associated Gene MIR137

被引:36
作者
Warburton, Alix [1 ]
Breen, Gerome [2 ,3 ,4 ]
Rujescu, Dan [5 ]
Bubb, Vivien J. [1 ]
Quinn, John P. [1 ]
机构
[1] Univ Liverpool, Dept Mol & Clin Pharmacol, Inst Translat Med, Liverpool L69 3BX, Merseyside, England
[2] Kings Coll London, MRC, Social Genet & Dev Psychiat Res Ctr, Inst Psychiat, London WC2R 2LS, England
[3] South London & Maudsley NHS Fdn Trust, Natl Inst Hlth Res, Biomed Res Ctr Mental Hlth, London SE5 8DF, England
[4] Kings Coll London, Inst Psychiat, London SE5 8DF, England
[5] Univ Halle Wittenberg, Dept Psychiat, D-06108 Halle, Germany
基金
英国生物技术与生命科学研究理事会;
关键词
cocaine; gene environment interaction; microRNA-137; variable number tandem repeat; RESTRICTIVE SILENCER FACTOR; SEROTONIN TRANSPORTER GENE; CELL LUNG-CANCER; TRANSCRIPTION FACTOR; AFFECTIVE-DISORDERS; VARIABLE NUMBER; IN-VIVO; EPIGENETIC REGULATION; FUNCTIONAL VARIANT; MONOAMINE-OXIDASE;
D O I
10.1093/schbul/sbu117
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
MIR137 has been identified as a candidate gene for schizophrenia from genome-wide association studies via association with an intronic single nucleotide polymorphism (SNP), rs1625579. The location of the SNP suggests one mechanism in which transcriptional or post-transcriptional regulation of miR-137 expression could underlie schizophrenia. We identified and validated a novel promoter of the MIR137 gene adjacent to miR-137 itself which can direct the expression of distinct mRNA isoforms encoding miR-137. Analysis of both endogenous gene expression and reporter gene assays determined that this internal promoter is regulated by repressor element-1 silencing transcription factor (REST), which has previously been associated with pathways linked to schizophrenia. Distinct isoforms of REST mediate differential expression at this locus, suggesting the relative levels of these isoforms are important for miR-137 expression profiles. The internal promoter contains a variable number tandem repeat (VNTR) domain adjacent to the pre-miR-137 sequence. The reporter gene activity directed by this promoter was modified by the genotype of the VNTR. Differential expression was also observed in response to cocaine, which is known to regulate the REST pathway in SH-SY5Y cells. Our data support the hypothesis that a "gene x environment" interaction could modify the level of miR-137 expression via this internal promoter and that the genotype of the VNTR could modulate transcriptional responses. We demonstrate that this promoter region is not in disequilibrium with rs1625579 and therefore would supply a distinct pathway to potentially alter miR-137 levels in response to environmental cues.
引用
收藏
页码:698 / 707
页数:10
相关论文
共 46 条
  • [1] Dual role of NRSF/REST in activation and repression of the glucocorticoid response
    Abramovitz, Lilach
    Shapira, Tamar
    Ben-Dror, Iris
    Dror, Vardit
    Granot, Limor
    Rousso, Tal
    Landoy, Elad
    Blau, Lior
    Thiel, Gerald
    Vardimon, Lily
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (01) : 110 - 119
  • [2] Combinatorial interaction between two human serotonin transporter gene variable number tandem repeats and their regulation by CTCF
    Ali, Fahad R.
    Vasiliou, Sylvia A.
    Haddley, Kate
    Paredes, Ursula M.
    Roberts, Julian C.
    Miyajima, Fabio
    Klenova, Elena
    Bubb, Vivien J.
    Quinn, John P.
    [J]. JOURNAL OF NEUROCHEMISTRY, 2010, 112 (01) : 296 - 306
  • [3] MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines
    Bemis, Lynne T.
    Chen, Robert
    Amato, Carol M.
    Classen, Elizabeth H.
    Robinson, Steven E.
    Coffey, David G.
    Erickson, Paul F.
    Shellman, Yiqun G.
    Robinson, William A.
    [J]. CANCER RESEARCH, 2008, 68 (05) : 1362 - 1368
  • [4] Modulation of orbitofrontal response to amphetamine by a functional variant of DAT1 and in vitro confirmation
    Brotons, O.
    O'Daly, O. G.
    Guindalini, C.
    Howard, M.
    Bubb, J.
    Barker, G.
    Dalton, J.
    Quinn, J.
    Murray, R. M.
    Breen, G.
    Shergill, S. S.
    [J]. MOLECULAR PSYCHIATRY, 2011, 16 (02) : 124 - 126
  • [5] Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes
    Bruce, AW
    Donaldson, IJ
    Wood, IC
    Yerbury, SA
    Sadowski, MI
    Chapman, M
    Göttgens, B
    Buckley, NJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (28) : 10458 - 10463
  • [6] REST - A MAMMALIAN SILENCER PROTEIN THAT RESTRICTS SODIUM-CHANNEL GENE-EXPRESSION TO NEURONS
    CHONG, JHA
    TAPIARAMIREZ, J
    KIM, S
    TOLEDOARAL, JJ
    ZHENG, YC
    BOUTROS, MC
    ALTSHULLER, YM
    FROHMAN, MA
    KRANER, SD
    MANDEL, G
    [J]. CELL, 1995, 80 (06) : 949 - 957
  • [7] Coulson JM, 2000, CANCER RES, V60, P1840
  • [8] Coulson Judy M, 2003, Methods Mol Med, V75, P335
  • [9] An intronic polymorphic domain often associated with susceptibility to affective disorders has allele dependent differential enhancer activity in embryonic stem cells
    Fiskerstrand, CE
    Lovejoy, EA
    Quinn, JP
    [J]. FEBS LETTERS, 1999, 458 (02) : 171 - 174
  • [10] A long AAAG repeat allele in the 5′ UTR of the ERR-γ gene is correlated with breast cancer predisposition and drives promoter activity in MCF-7 breast cancer cells
    Galindo, C. L.
    McCormick, J. F.
    Bubb, V. J.
    Alkadem, D. H. Abid
    Li, Long-Shan
    McIver, L. J.
    George, A. C.
    Boothman, D. A.
    Quinn, J. P.
    Skinner, M. A.
    Garner, H. R.
    [J]. BREAST CANCER RESEARCH AND TREATMENT, 2011, 130 (01) : 41 - 48