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

Journal Article (Journal 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.

Full Text

Duke Authors

Cited Authors

  • Afek, A; Tagliafierro, L; Glenn, OC; Lukatsky, DB; Gordan, R; Chiba-Falek, O

Published Date

  • August 2018

Published In

Volume / Issue

  • 19 / 3

Start / End Page

  • 135 - 144

PubMed ID

  • 29730780

Pubmed Central ID

  • PMC6054541

Electronic International Standard Serial Number (EISSN)

  • 1364-6753

Digital Object Identifier (DOI)

  • 10.1007/s10048-018-0546-8


  • eng

Conference Location

  • United States