Feifei Li
Zhihua Zhang
a CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, China National Center for Bioinformation, Beijing 100101, China;
b School of Life Science, University of Chinese Academy of Sciences, Beijing 100101, China;
c School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing 100101, China
Funds: This work was supported by the National Natural Science Foundation of China of China (91940304, 31871331, 31671342), Beijing Natural Science Foundation (Z200021), Special Investigation on Science and Technology Basic Resources of MOST, China (2019FY100102), the National Key R&D Program of China (2018YFC2000400), and the Beijing Advanced Discipline Fund (115200S001). We are also grateful to Dr. Yang Yu, Dr. Jing Li, Dr. Junfeng Liu, Dr. Bingxiang Xu, Dr. Hui Zhang, Yiqun Zhang, and Xiao Zhang for helpful discussions. Mr. David Martin performed English language editorial services.
Received Date: 2021-05-27
Accepted Date:2021-07-07
Rev Recd Date:2021-06-24
Publish Date:2021-11-20
Abstract
Abstract
Enhancers modulate gene expression by interacting with promoters. Models of enhancer-promoter interactions (EPIs) in the literature involve the activity of many components, including transcription factors and nucleic acid. However, the role that sequence similarity plays in EPIs remains largely unexplored. Herein, we report that Alu-derived sequences dominate sequence similarity between enhancers and promoters. After rejecting alternative DNA:DNA and DNA:RNA triplex models, we propose that enhancer-associated RNAs (eRNAs) may directly contact their targeted promoters by forming trans-acting R-loops at those Alu sequences. We show how the characteristic distribution of functional genomic data, such as RNA-DNA proximate ligation reads, binding of transcription factors, and RNA-binding proteins, all align with the Alu sequences of EPIs. We also show that these aligned Alu sequences may be subject to the constraint of coevolution, further implying the functional significance of these R-loop hybrids. Finally, our results imply that eRNA and Alu elements associate in a manner previously unrecognized in EPIs and the evolution of gene regulation networks in mammals.Keywords: Alu,
Enhancer-promoter interaction,
eRNA,
R-loop
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