HIF1α-AS1 is a DNA:DNA:RNA triplex-forming lncRNA interacting with the HUSH complex

Matthias S. Leisegang, Jasleen Kaur Bains, Sandra Seredinski, James A. Oo, Nina M. Krause, Chao-Chung Kuo, Stefan Günther, Nevcin Sentürk Cetin, Timothy Warwick, Can Cao, Frederike Boos, Judit Izquierdo Ponce, Shaza Haydar, Rebecca Bednarz, Chanil Valasarajan, Dominik C. Fuhrmann, Jens Preussner, Mario Looso, Soni S. Pullamsetti, Marcel H. Schulz, Hendrik R. A. Jonker, Christian Richter, Flávia Rezende, Ralf Gilsbach, Beatrice Pflüger-Müller, Ilka Wittig, Ingrid Grummt, Teodora Ribarska, Ivan G. Costa, Harald Schwalbe () and Ralf P. Brandes ()
Additional contact information
Matthias S. Leisegang: Goethe University
Jasleen Kaur Bains: Goethe University
Sandra Seredinski: Goethe University
James A. Oo: Goethe University
Nina M. Krause: Goethe University
Chao-Chung Kuo: Joint Research Center for Computational Biomedicine, RWTH Aachen Medical Faculty
Stefan Günther: Max Planck Institute for Heart and Lung Research
Nevcin Sentürk Cetin: German Cancer Research Center DKFZ-ZMBH
Timothy Warwick: Goethe University
Can Cao: Goethe University
Frederike Boos: Goethe University
Judit Izquierdo Ponce: Goethe University
Shaza Haydar: Goethe University
Rebecca Bednarz: Goethe University
Chanil Valasarajan: Max Planck Institute for Heart and Lung Research
Dominik C. Fuhrmann: Goethe University
Jens Preussner: Max Planck Institute for Heart and Lung Research
Mario Looso: Max Planck Institute for Heart and Lung Research
Soni S. Pullamsetti: Max Planck Institute for Heart and Lung Research
Marcel H. Schulz: Partner site RheinMain
Hendrik R. A. Jonker: Goethe University
Christian Richter: Goethe University
Flávia Rezende: Goethe University
Ralf Gilsbach: Goethe University
Beatrice Pflüger-Müller: Goethe University
Ilka Wittig: Goethe University
Ingrid Grummt: German Cancer Research Center DKFZ-ZMBH
Teodora Ribarska: German Cancer Research Center DKFZ-ZMBH
Ivan G. Costa: Joint Research Center for Computational Biomedicine, RWTH Aachen Medical Faculty
Harald Schwalbe: Goethe University
Ralf P. Brandes: Goethe University

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract DNA:DNA:RNA triplexes that are formed through Hoogsteen base-pairing of the RNA in the major groove of the DNA duplex have been observed in vitro, but the extent to which these interactions occur in cells and how they impact cellular functions remains elusive. Using a combination of bioinformatic techniques, RNA/DNA pulldown and biophysical studies, we set out to identify functionally important DNA:DNA:RNA triplex-forming long non-coding RNAs (lncRNA) in human endothelial cells. The lncRNA HIF1α-AS1 was retrieved as a top hit. Endogenous HIF1α-AS1 reduces the expression of numerous genes, including EPH Receptor A2 and Adrenomedullin through DNA:DNA:RNA triplex formation by acting as an adapter for the repressive human silencing hub complex (HUSH). Moreover, the oxygen-sensitive HIF1α-AS1 is down-regulated in pulmonary hypertension and loss-of-function approaches not only result in gene de-repression but also enhance angiogenic capacity. As exemplified here with HIF1α-AS1, DNA:DNA:RNA triplex formation is a functionally important mechanism of trans-acting gene expression control.

Date: 2022
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DOI: 10.1038/s41467-022-34252-2

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