@article{d7202d6e0ac94b668f8ac0501f75f91c,
title = "High-throughput characterization of the role of non-B DNA motifs on promoter function",
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.",
keywords = "G-quadruplex, MPRA, Z-DNA, mutations, non-B DNA, promoter",
author = "Ilias Georgakopoulos-Soares and Jesus Victorino and Parada, {Guillermo E.} and Vikram Agarwal and Jingjing Zhao and Wong, {Hei Yuen} and Umar, {Mubarak Ishaq} and Orry Elor and Allan Muhwezi and An, {Joon Yong} and Sanders, {Stephan J.} and Kwok, {Chun Kit} and Fumitaka Inoue and Martin Hemberg and Nadav Ahituv",
note = "Funding Information: This work is supported by the National Human Genome Research Institute ( 1UM1HG009408 , R01HG010333 , 1R21HG010065 , UM1HG011966 , and 1R21HG010683 to N.A.), the National Institute of Mental Health ( 1R01MH109907 and 1U01MH116438 to N.A.), and the National Heart, Lung, and Blood Institute ( R35HL145235 to N.A.). G.E.P. and M.H. were supported by a core grant from the Wellcome Trust . Funding for open access charge was provided by NHGRI . The C.K.K. lab is supported by the Shenzhen Basic Research Project ( JCYJ20180507181642811 ); the Research Grants Council of the Hong Kong SAR , China Projects ( CityU 11100421 , CityU 11101519 , CityU 11100218 , and N_CityU110/17 ); the Croucher Foundation Project ( 9509003 ); the State Key Laboratory of Marine Pollution Director Discretionary Fund ; City University of Hong Kong projects ( 7005503 , 9667222 , and 9680261 ) to C.K.K.; and National Research Foundation of Korea grant 2020R1C1C1003426 (to J.-Y.A.). O.E. is supported by a California Institute of Regenerative Medicine fellowship ( SFSU EDUC2-08391 ). The sequencing was carried by the DNA Technologies and Expression Analysis Core at the UC Davis Genome Center, supported by NIH Shared Instrumentation grant 1S10OD010786-01 . Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = apr,
day = "13",
doi = "10.1016/j.xgen.2022.100111",
language = "English",
volume = "2",
journal = "Cell Genomics",
issn = "2666-979X",
publisher = "Cell Press",
number = "4",
}