High-throughput Characterization of the Role of Non-B DNA Motifs on Promoter Function

Overview

Journal Cell Genom

Date 2022 May 16

PMID 35573091

Authors

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

Affiliations

Soon will be listed here.

Abstract

lternative 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.

Citing Articles

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