A searchable atlas of pathogen-sensitive lncRNA networks in human macrophages

Nils Schmerer, Harshavardhan Janga, Michelle Aillaud, Janina Hoffmann, Marina Aznaourova, Sarah Wende, Henrike Steding, Luke D. Halder, Michael Uhl, Fabian Boldt, Thorsten Stiewe, Andrea Nist, Lukas Jerrentrup, Andreas Kirschbaum, Clemens Ruppert, Oliver Rossbach, Evgenia Ntini, Annalisa Marsico, Chanil Valasarajan, Rolf Backofen, Uwe Linne, Soni S. Pullamsetti, Bernd Schmeck and Leon N. Schulte ()
Additional contact information
Nils Schmerer: Philipps University Marburg
Harshavardhan Janga: Philipps University Marburg
Michelle Aillaud: Philipps University Marburg
Janina Hoffmann: Philipps University Marburg
Marina Aznaourova: Philipps University Marburg
Sarah Wende: Philipps University Marburg
Henrike Steding: Philipps University Marburg
Luke D. Halder: Philipps University Marburg
Michael Uhl: University of Freiburg
Fabian Boldt: Philipps University Marburg
Thorsten Stiewe: German Center for Lung Research (DZL)
Andrea Nist: University of Marburg
Lukas Jerrentrup: Philipps University Marburg
Andreas Kirschbaum: University Hospital Giessen and Marburg (UKGM)
Clemens Ruppert: German Center for Lung Research (DZL)
Oliver Rossbach: Justus Liebig University Giessen
Evgenia Ntini: Max Planck Institute for Molecular Genetics
Annalisa Marsico: Max Planck Institute for Molecular Genetics
Chanil Valasarajan: Universities of Giessen and Marburg Lung Center (UGMLC)
Rolf Backofen: University of Freiburg
Uwe Linne: Philipps University
Soni S. Pullamsetti: German Center for Lung Research (DZL)
Bernd Schmeck: Philipps University Marburg
Leon N. Schulte: Philipps University Marburg

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Long noncoding RNAs (lncRNA) are crucial yet underexplored regulators of human immunity. Here we develop GRADR, a method integrating gradient profiling with RNA-binding proteome analysis, to map the protein interactomes of all expressed RNAs in a single experiment to study mechanisms of lncRNA-mediated regulation of human primary macrophages. Applying GRADR alongside CRISPR-multiomics, we reveal a network of NFκB-dependent lncRNAs, including LINC01215, AC022816.1 and ROCKI, which modulate distinct aspects of macrophage immunity, particularly through interactions with mRNA-processing factors, such as hnRNP proteins. We further uncover the function of ROCKI in repressing the messenger of the anti-inflammatory GATA2 transcription factor, thus promoting macrophage activation. Lastly, all data are consolidated in the SMyLR web interface, a searchable reference catalog for exploring lncRNA functions and pathway-dependencies in immune cells. Our results thus not only highlight the important functions of lncRNAs in immune regulation, but also provide a rich resource for lncRNA studies.

Date: 2025
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DOI: 10.1038/s41467-025-60084-x

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