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

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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.

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Acknowledgements

We thank the Layton Aging and Alzheimer’s Disease Center at Oregon Health and Science University for providing us with the brain tissues, and Dr. Randy Woltjer for his assistance in obtaining the required brain samples for the study.

Funding

This work was funded in part by the Holland-Trice award (to O.C-F. and R.G.), the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) (R01 NS085011 to O.C-F.), and the National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) (R01 GM117106 to R.G.).

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Authors and Affiliations

  1. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, 27710, USA

    A. Afek & R. Gordan

  2. Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27710, USA

    A. Afek, L. Tagliafierro, O.C. Glenn, R. Gordan & O. Chiba-Falek

  3. Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA

    L. Tagliafierro, O.C. Glenn & O. Chiba-Falek

  4. Department of Chemistry, Ben-Gurion University of the Negev, 8410501, Beersheba, Israel

    D.B. Lukatsky

  5. Department of Computer Science, Duke University, Durham, NC, 27708, USA

    R. Gordan

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  1. A. Afek
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  2. L. Tagliafierro
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  3. O.C. Glenn
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  4. D.B. Lukatsky
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  5. R. Gordan
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  6. O. Chiba-Falek
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Corresponding authors

Correspondence to R. Gordan or O. Chiba-Falek.

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The projects were approved by the Duke Institutional Review Board and followed appropriate ethical protocols, and all experiments were performed in accordance with relevant guidelines and regulations.

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The authors declare that they have no competing interests.

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Afek, A., Tagliafierro, L., Glenn, O. et al. Toward deciphering the mechanistic role of variations in the Rep1 repeat site in the transcription regulation of SNCA gene. Neurogenetics 19, 135–144 (2018). https://doi.org/10.1007/s10048-018-0546-8

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  • DOI: https://doi.org/10.1007/s10048-018-0546-8

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