Hi-C data from murine bone marrow derived macrophages to study chimeric RNAs

However, whether mRNA from distant genes can undergo trans-splicing to generate functionally relevant chimeric transcripts has remained unclear. Here, we developed a pipeline combining long-read direct RNA sequencing with unbiased and targeted validation to systematically identify chimeric transcripts in macrophages.

Chromatin conformation capture studies revealed that inflammation induces interchromosomal DNA interactions, positioning parent genes proximally to facilitate chimeric RNA formation. Notably, we identified a protein-coding chimeric mRNA representing a fusion between the pore forming protein gasdermin D (GSDMD) and a C-terminal domain translated out-of-frame from Tmem106a (GSDMD:TMEM106A). We show that inflammasome priming signals upregulate GSDMD:TMEM106A, with the protein localizing to the plasma membrane, where it remains inactive.