High-throughput characterization of the role of non-B DNA motifs on promoter function.
Parada, Guillermo E
Wong, Hei Yuen
Umar, Mubarak Ishaq
Sanders, Stephan J
Kwok, Chun Kit
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Georgakopoulos-Soares, I., Victorino, J., Parada, G. E., Agarwal, V., Zhao, J., Wong, H. Y., Umar, M. I., et al. (2022). High-throughput characterization of the role of non-B DNA motifs on promoter function.. Cell Genom, 2 (4) https://doi.org/10.1016/j.xgen.2022.100111
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.
NHGRI NIH HHS (R21 HG010683, UM1 HG011966, UM1 HG009408, R21 HG010065)
NIMH NIH HHS (R01 MH109907, U01 MH116438)
NHLBI NIH HHS (R35 HL145235)
External DOI: https://doi.org/10.1016/j.xgen.2022.100111
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338180
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/