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
- Leon N. Schulte
2025-05-21
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.