, Volume 19, Issue 3, pp 135–144 | Cite as

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

  • A. Afek
  • L. Tagliafierro
  • O.C. Glenn
  • D.B. Lukatsky
  • R. Gordan
  • O. Chiba-Falek
Original Article


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.


GATA SNCA Simple sequence repeat (SSR) variants Parkinson’s disease Transcription factors 



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.


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.).

Compliance with ethical standards

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.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

10048_2018_546_MOESM1_ESM.pdf (514 kb)
ESM 1 (PDF 513 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biostatistics and BioinformaticsDuke University Medical CenterDurhamUSA
  2. 2.Center for Genomic and Computational BiologyDuke University Medical CenterDurhamUSA
  3. 3.Department of NeurologyDuke University Medical CenterDurhamUSA
  4. 4.Department of ChemistryBen-Gurion University of the NegevBeershebaIsrael
  5. 5.Department of Computer ScienceDuke UniversityDurhamUSA

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