nach oben

Neurogenetics

Erschienen in:

05.05.2018 | Original Article

Toward deciphering the mechanistic role of variations in the Rep1 repeat site in the transcription regulation of SNCA gene

verfasst von: A. Afek, L. Tagliafierro, O.C. Glenn, D.B. Lukatsky, R. Gordan, O. Chiba-Falek

Erschienen in: Neurogenetics | Ausgabe 3/2018

Einloggen, um Zugang zu erhalten

Abstract

Short structural variants—variants other than single nucleotide polymorphisms—are hypothesized to contribute to many complex diseases, possibly by modulating gene expression. However, the molecular mechanisms by which noncoding short structural variants exert their effects on gene regulation have not been discovered. Here, we study simple sequence repeats (SSRs), a common class of short structural variants. Previously, we showed that repetitive sequences can directly influence the binding of transcription factors to their proximate recognition sites, a mechanism we termed non-consensus binding. In this study, we focus on the SSR termed Rep1, which was associated with Parkinson’s disease (PD) and has been implicated in the cis-regulation of the PD-risk SNCA gene. We show that Rep1 acts via the non-consensus binding mechanism to affect the binding of transcription factors from the GATA and ELK families to their specific sites located right next to the Rep1 repeat. Next, we performed an expression analysis to further our understanding regarding the GATA and ELK family members that are potentially relevant for SNCA transcriptional regulation in health and disease. Our analysis indicates a potential role for GATA2, consistent with previous reports. Our study proposes non-consensus transcription factor binding as a potential mechanism through which noncoding repeat variants could exert their pathogenic effects by regulating gene expression.

Nur mit Berechtigung zugänglich

Mirkin SM (2007) Expandable DNA repeats and human disease. Nature 447:932–940CrossRefPubMed

Pearson CE, Nichol Edamura K, Cleary JD (2005) Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6:729–742CrossRefPubMed

Willems T, Gymrek M, Highnam G, Genomes Project C, Mittelman D, Erlich Y (2014) The landscape of human STR variation. Genome Res 24:1894–1904CrossRefPubMedPubMedCentral

Gymrek M, Willems T, Guilmatre A, Zeng H, Markus B, Georgiev S et al (2016) Abundant contribution of short tandem repeats to gene expression variation in humans. Nat Genet 48:22–29CrossRefPubMed

Akai J, Kimura A, Hata RI (1999) Transcriptional regulation of the human type I collagen alpha2 (COL1A2) gene by the combination of two dinucleotide repeats. Gene 239:65–73CrossRefPubMed

Chiba-Falek O, Nussbaum RL (2001) Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet 10:3101–3109CrossRefPubMed

Okladnova O, Syagailo YV, Tranitz M, Stober G, Riederer P, Mossner R et al (1998) A promoter-associated polymorphic repeat modulates PAX-6 expression in human brain. Biochem Biophys Res Commun 248:402–405CrossRefPubMed

Peters DG, Kassam A, St Jean PL, Yonas H, Ferrell RE (1999) Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm. Stroke 30:2612–2616CrossRefPubMed

Searle S, Blackwell JM (1999) Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility. J Med Genet 36:295–299PubMedPubMedCentral

10.

Shimajiri S, Arima N, Tanimoto A, Murata Y, Hamada T, Wang KY et al (1999) Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene. FEBS Lett 455:70–74CrossRefPubMed

11.

Hefferon TW, Groman JD, Yurk CE, Cutting GR (2004) A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing. Proc Natl Acad Sci U S A 101:3504–3509CrossRefPubMedPubMedCentral

12.

Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R et al (2006) Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 296:661–670CrossRefPubMed

13.

Xia Y, Rohan de Silva HA, Rosi BL, Yamaoka LH, Rimmler JB, Pericak-Vance MA et al (1996) Genetic studies in Alzheimer’s disease with an NACP/alpha-synuclein polymorphism. Ann Neurol 40:207–215CrossRefPubMed

14.

Touchman JW, Dehejia A, Chiba-Falek O, Cabin DE, Schwartz JR, Orrison BM et al (2001) Human and mouse alpha-synuclein genes: comparative genomic sequence analysis and identification of a novel gene regulatory element. Genome Res 11:78–86CrossRefPubMedPubMedCentral

15.

Goldman SM, Umbach DM, Kamel F, Tanner CM (2015) Head injury, alpha-synuclein Rep1 and Parkinson’s disease: a meta-analytic view of gene-environment interaction. Eur J Neurol 22:e75CrossRefPubMed

16.

Kay DM, Factor SA, Samii A, Higgins DS, Griffith A, Roberts JW et al (2008) Genetic association between alpha-synuclein and idiopathic Parkinson’s disease. Am J Med Genet B Neuropsychiatr Genet 147B:1222–1230CrossRefPubMed

17.

Farrer M, Maraganore DM, Lockhart P, Singleton A, Lesnick TG, de Andrade M et al (2001) alpha-Synuclein gene haplotypes are associated with Parkinson’s disease. Hum Mol Genet 10:1847–1851CrossRefPubMed

18.

Mizuta I, Nishimura M, Mizuta E, Yamasaki S, Ohta M, Kuno S (2002) Meta-analysis of alpha synuclein/ NACP polymorphism in Parkinson’s disease in Japan. J Neurol Neurosurg Psychiatry 73:350CrossRefPubMedPubMedCentral

19.

Mellick GD, Maraganore DM, Silburn PA (2005) Australian data and meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a risk factor for Parkinson’s disease. Neurosci Lett 375:112–116CrossRefPubMed

20.

Linnertz C, Saucier L, Ge D, Cronin KD, Burke JR, Browndyke JN et al (2009) Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues. PLoS One 4:e7480CrossRefPubMedPubMedCentral

21.

Chiba-Falek O, Touchman JW, Nussbaum RL (2003) Functional analysis of intra-allelic variation at NACP-Rep1 in the alpha-synuclein gene. Hum Genet 113:426–431CrossRefPubMed

22.

Cronin KD, Ge D, Manninger P, Linnertz C, Rossoshek A, Orrison BM et al (2009) Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein in transgenic mouse brain. Hum Mol Genet 18:3274–3285CrossRefPubMedPubMedCentral

23.

Saul R, Lutz MW, Burns DK, Roses AD, Chiba-Falek O (2016) The SSV evaluation system: a tool to prioritize short structural variants for studies of possible regulatory and causal variants. Hum Mutat 37:877–883CrossRefPubMedPubMedCentral

24.

Afek A, Cohen H, Barber-Zucker S, Gordan R, Lukatsky DB (2015) Nonconsensus protein binding to repetitive DNA sequence elements significantly affects eukaryotic genomes. PLoS Comput Biol 11:e1004429CrossRefPubMedPubMedCentral

25.

Afek A, Schipper JL, Horton J, Gordan R, Lukatsky DB (2014) Protein-DNA binding in the absence of specific base-pair recognition. Proc Natl Acad Sci U S A 111:17140–17145CrossRefPubMedPubMedCentral

26.

Berger MF, Philippakis AA, Qureshi AM, He FS, Estep PW 3rd, Bulyk ML (2006) Compact, universal DNA microarrays to comprehensively determine transcription-factor binding site specificities. Nat Biotechnol 24:1429–1435CrossRefPubMedPubMedCentral

27.

Hume MA, Barrera LA, Gisselbrecht SS, Bulyk ML (2015) UniPROBE, update 2015: new tools and content for the online database of protein-binding microarray data on protein-DNA interactions. Nucleic Acids Res 43:D117–D122CrossRefPubMed

28.

Weirauch MT, Yang A, Albu M, Cote AG, Montenegro-Montero A, Drewe P et al (2014) Determination and inference of eukaryotic transcription factor sequence specificity. Cell 158:1431–1443CrossRefPubMedPubMedCentral

29.

Wei GH, Badis G, Berger MF, Kivioja T, Palin K, Enge M et al (2010) Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo. EMBO J 29:2147–2160CrossRefPubMedPubMedCentral

30.

Nardelli J, Thiesson D, Fujiwara Y, Tsai FY, Orkin SH (1999) Expression and genetic interaction of transcription factors GATA-2 and GATA-3 during development of the mouse central nervous system. Dev Biol 210:305–321CrossRefPubMed

31.

Scherzer CR, Grass JA, Liao Z, Pepivani I, Zheng B, Eklund AC et al (2008) GATA transcription factors directly regulate the Parkinson’s disease-linked gene alpha-synuclein. Proc Natl Acad Sci U S A 105:10907–10912CrossRefPubMedPubMedCentral

32.

Brenner S, Wersinger C, Gasser T (2015) Transcriptional regulation of the alpha-synuclein gene in human brain tissue. Neurosci Lett 599:140–145CrossRefPubMed

33.

Berger MF, Bulyk ML (2009) Universal protein-binding microarrays for the comprehensive characterization of the DNA-binding specificities of transcription factors. Nat Protoc 4:393–411CrossRefPubMedPubMedCentral

34.

Barrera LA, Vedenko A, Kurland JV, Rogers JM, Gisselbrecht SS, Rossin EJ et al (2016) Survey of variation in human transcription factors reveals prevalent DNA binding changes. Science 351:1450–1454CrossRefPubMedPubMedCentral

35.

Gordan R, Hartemink AJ, Bulyk ML (2009) Distinguishing direct versus indirect transcription factor-DNA interactions. Genome Res 19:2090–2100CrossRefPubMedPubMedCentral

36.

Chiba-Falek O, Lopez GJ, Nussbaum RL (2006) Levels of alpha-synuclein mRNA in sporadic Parkinson disease patients. Mov Disord 21:1703–1708CrossRefPubMed

37.

Linnertz C, Anderson L, Gottschalk W, Crenshaw D, Lutz MW, Allen J et al (2014) The cis-regulatory effect of an Alzheimer’s disease-associated poly-T locus on expression of TOMM40 and apolipoprotein E genes. Alzheimer's Dementia : J Alzheimer's Assoc 10:541–551CrossRef

38.

Linnertz C, Lutz MW, Ervin JF, Allen J, Miller NR, Welsh-Bohmer KA et al (2014) The genetic contributions of SNCA and LRRK2 genes to Lewy body pathology in Alzheimer’s disease. Hum Mol Genet 23:4814–4821CrossRefPubMedPubMedCentral

39.

Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J et al (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841CrossRefPubMed

40.

Farrer M, Kachergus J, Forno L, Lincoln S, Wang DS, Hulihan M et al (2004) Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 55:174–179CrossRefPubMed

41.

Miller DW, Hague SM, Clarimon J, Baptista M, Gwinn-Hardy K, Cookson MR et al (2004) Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology 62:1835–1838CrossRefPubMed

42.

Grundemann J, Schlaudraff F, Haeckel O, Liss B (2008) Elevated alpha-synuclein mRNA levels in individual UV-laser-microdissected dopaminergic substantia nigra neurons in idiopathic Parkinson’s disease. Nucleic Acids Res 36:e38CrossRefPubMedPubMedCentral

43.

Rockenstein E, Hansen LA, Mallory M, Trojanowski JQ, Galasko D, Masliah E (2001) Altered expression of the synuclein family mRNA in Lewy body and Alzheimer’s disease. Brain Res 914:48–56CrossRefPubMed

44.

Asi YT, Simpson JE, Heath PR, Wharton SB, Lees AJ, Revesz T et al (2014) Alpha-synuclein mRNA expression in oligodendrocytes in MSA. Glia 62:964–970CrossRefPubMedPubMedCentral

45.

Lutz MW, Saul R, Linnertz C, Glenn OC, Roses AD, Chiba-Falek O (2015) A cytosine-thymine (CT)-rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer’s disease and affects SNCA expression. Alzheimer's Dementia : J Alzheimer's Assoc. 11:1133–1143CrossRef

46.

Soldner F, Stelzer Y, Shivalila CS, Abraham BJ, Latourelle JC, Barrasa MI et al (2016) Parkinson-associated risk variant in distal enhancer of alpha-synuclein modulates target gene expression. Nature 533:95–99CrossRefPubMedPubMedCentral

47.

Tagliafierro L, Glenn OC, Zamora ME, Beach TG, Woltjer RL, Lutz MW et al (2017) Genetic analysis of alpha-synuclein 3′ untranslated region and its corresponding microRNAs in relation to Parkinson's compared to dementia with Lewy bodies. Alzheimers Dement

48.

Bonhoure N, Bounova G, Bernasconi D, Praz V, Lammers F, Canella D et al (2014) Quantifying ChIP-seq data: a spiking method providing an internal reference for sample-to-sample normalization. Genome Res 24:1157–1168CrossRefPubMedPubMedCentral

49.

Lutz MW, Saul R, Linnertz C, Glenn OC, Roses AD, Chiba-Falek O. A cytosine-thymine (CT)-rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer's disease and affects SNCA expression. Alzheimer's Dementia :J Alzheimer’s Assoc. 2015

50.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−delta delta C(T)) method. Methods (San Diego, Calif) 25:402–408CrossRef

51.

Gordan R, Shen N, Dror I, Zhou T, Horton J, Rohs R et al (2013) Genomic regions flanking E-box binding sites influence DNA binding specificity of bHLH transcription factors through DNA shape. Cell Rep 3:1093–1104CrossRefPubMedPubMedCentral

52.

Mordelet F, Horton J, Hartemink AJ, Engelhardt BE, Gordan R (2013) Stability selection for regression-based models of transcription factor-DNA binding specificity. Bioinformatics 29:i117–i125CrossRefPubMedPubMedCentral

Titel: Toward deciphering the mechanistic role of variations in the Rep1 repeat site in the transcription regulation of SNCA gene
verfasst von: A. Afek
L. Tagliafierro
O.C. Glenn
D.B. Lukatsky
R. Gordan
O. Chiba-Falek
Publikationsdatum: 05.05.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Neurogenetics / Ausgabe 3/2018
Print ISSN: 1364-6745
Elektronische ISSN: 1364-6753
DOI: https://doi.org/10.1007/s10048-018-0546-8

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Frühe Alzheimertherapie lohnt sich

25.04.2024 AAN-Jahrestagung 2024 Nachrichten

Ist die Tau-Last noch gering, scheint der Vorteil von Lecanemab besonders groß zu sein. Und beginnen Erkrankte verzögert mit der Behandlung, erreichen sie nicht mehr die kognitive Leistung wie bei einem früheren Start. Darauf deuten neue Analysen der Phase-3-Studie Clarity AD.

Viel Bewegung in der Parkinsonforschung

25.04.2024 Parkinson-Krankheit Nachrichten

Neue arznei- und zellbasierte Ansätze, Frühdiagnose mit Bewegungssensoren, Rückenmarkstimulation gegen Gehblockaden – in der Parkinsonforschung tut sich einiges. Auf dem Deutschen Parkinsonkongress ging es auch viel um technische Innovationen.

Demenzkranke durch Antipsychotika vielfach gefährdet

23.04.2024 Demenz Nachrichten

Wenn Demenzkranke aufgrund von Symptomen wie Agitation oder Aggressivität mit Antipsychotika behandelt werden, sind damit offenbar noch mehr Risiken verbunden als bislang angenommen.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2018

Clinical and genetic study of Tunisian families with genetic generalized epilepsy: contribution of CACNA1H and MAST4 genes

Compound heterozygous mutations in two different domains of ALDH18A1 do not affect the amino acid levels in a patient with hereditary spastic paraplegia

R106C TFG variant causes infantile neuroaxonal dystrophy “plus” syndrome

Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings

FUS(1-359) transgenic mice as a model of ALS: pathophysiological and molecular aspects of the proteinopathy