High-throughput characterization of the role of non-B DNA motifs on promoter function

Ilias Georgakopoulos-Soares, Jesus Victorino, Guillermo E. Parada, Vikram Agarwal, Jingjing Zhao, Hei Yuen Wong, Mubarak Ishaq Umar, Orry Elor, Allan Muhwezi, Joon Yong An, Stephan J. Sanders, Chun Kit Kwok, Fumitaka Inoue, Martin Hemberg, Nadav Ahituv

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Alternative DNA conformations, termed non-B DNA structures, can affect transcription, but the underlying mechanisms and their functional impact have not been systematically characterized. Here, we used computational genomic analyses coupled with massively parallel reporter assays (MPRAs) to show that certain non-B DNA structures have a substantial effect on gene expression. Genomic analyses found that non-B DNA structures at promoters harbor an excess of germline variants. Analysis of multiple MPRAs, including a promoter library specifically designed to perturb non-B DNA structures, functionally validated that Z-DNA can significantly affect promoter activity. We also observed that biophysical properties of non-B DNA motifs, such as the length of Z-DNA motifs and the orientation of G-quadruplex structures relative to transcriptional direction, have a significant effect on promoter activity. Combined, their higher mutation rate and functional effect on transcription implicate a subset of non-B DNA motifs as major drivers of human gene-expression-associated phenotypes.

Original languageEnglish
Article number100111
JournalCell Genomics
Volume2
Issue number4
DOIs
Publication statusPublished - 2022 Apr 13

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

Keywords

  • G-quadruplex
  • MPRA
  • Z-DNA
  • mutations
  • non-B DNA
  • promoter

ASJC Scopus subject areas

  • Genetics
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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