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Schmerer, N.* ; Janga, H.* ; Aillaud, M.* ; Hoffmann, J.* ; Aznaourova, M.* ; Wende, S.* ; Steding, H.* ; Halder, L.D.* ; Uhl, M.* ; Boldt, F.* ; Stiewe, T.* ; Nist, A.* ; Jerrentrup, L.* ; Kirschbaum, A.* ; Ruppert, C.* ; Rossbach, O.* ; Ntini, E.* ; Marsico, A. ; Valasarajan, C.* ; Backofen, R.* ; Linne, U.* ; Pullamsetti, S.S.* ; Schmeck, B.* ; Schulte, L.N.*

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

Nat. Commun. 16:4733 (2025)

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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.

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