Complementary Alu sequences mediate enhancer–promoter selectivity

Liang Liang, Changchang Cao, Lei Ji, Zhaokui Cai, Di Wang, Rong Ye, Juan Chen, Xiaohua Yu, Jie Zhou, Zhibo Bai, Ruoyan Wang, Xianguang Yang, Ping Zhu and Yuanchao Xue ()
Additional contact information
Liang Liang: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Changchang Cao: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Lei Ji: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Zhaokui Cai: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Di Wang: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Rong Ye: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Juan Chen: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Xiaohua Yu: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Jie Zhou: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Zhibo Bai: Henan Normal University
Ruoyan Wang: Henan Normal University
Xianguang Yang: Henan Normal University
Ping Zhu: Southern Medical University
Yuanchao Xue: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences

Nature, 2023, vol. 619, issue 7971, 868-875

Abstract: Abstract Enhancers determine spatiotemporal gene expression programs by engaging with long-range promoters1–4. However, it remains unknown how enhancers find their cognate promoters. We recently developed a RNA in situ conformation sequencing technology to identify enhancer–promoter connectivity using pairwise interacting enhancer RNAs and promoter-derived noncoding RNAs5,6. Here we apply this technology to generate high-confidence enhancer–promoter RNA interaction maps in six additional cell lines. Using these maps, we discover that 37.9% of the enhancer–promoter RNA interaction sites are overlapped with Alu sequences. These pairwise interacting Alu and non-Alu RNA sequences tend to be complementary and potentially form duplexes. Knockout of Alu elements compromises enhancer–promoter looping, whereas Alu insertion or CRISPR–dCasRx-mediated Alu tethering to unregulated promoter RNAs can create new loops to homologous enhancers. Mapping 535,404 noncoding risk variants back to the enhancer–promoter RNA interaction maps enabled us to construct variant-to-function maps for interpreting their molecular functions, including 15,318 deletions or insertions in 11,677 Alu elements that affect 6,497 protein-coding genes. We further demonstrate that polymorphic Alu insertion at the PTK2 enhancer can promote tumorigenesis. Our study uncovers a principle for determining enhancer–promoter pairing specificity and provides a framework to link noncoding risk variants to their molecular functions.

Date: 2023
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DOI: 10.1038/s41586-023-06323-x

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