BOSTON — Mammalian cells can stitch instructions from genes on different chromosomes into chimeric messenger RNAs that make functional hybrid proteins, Harvard Medical School researchers reported Sept. 2 in Nature.
For decades, textbooks treated each of the roughly 20,000 human genes as encoding one kind of protein, with isoform diversity arising mainly through cis-splicing within a single locus. Using long-read direct RNA sequencing, Ruaidhri Jackson’s team compiled what he calls a “dark genome” library of more than 30,000 chimeric transcripts seen at least once in mammalian cells and profiled nearly 400 regulated by inflammatory signals in human and mouse immune cells.
Chromatin conformation capture showed inflammation can loop chromosomes together, placing distant parent genes near each other so a fused mRNA can form. One protein-coding chimera fuses the pore-forming inflammasome effector gasdermin D (GSDMD) with an out-of-frame C-terminal domain from Tmem106a. The GSDMD-TMEM106A protein localizes to the plasma membrane, partners with canonical GSDMD N termini after inflammasome activation, and speeds pore formation and IL-1 beta release during pyroptosis — but cannot open membranes without GSDMD.
In mice, loss of the chimera impaired antibacterial defense while reducing lethal sepsis risk; overexpression strengthened host protection but raised sepsis lethality. The authors argue chimeric RNAs are regulated players in immunity and a possible therapeutic target class, while leaving intact the broader picture that most proteins still arise from single genes.
Sources: Nature; Harvard / phys.org.
