cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing

Carolina Uggenti, Alice Lepelley, Marine Depp, Andrew P. Badrock, Mathieu P. Rodero, Marie-Thérèse El-Daher, Gillian I. Rice, Somdutta Dhir, Ann P. Wheeler, Ashish Dhir, Waad Albawardi, Marie-Louise Frémond, Luis Seabra, Jennifer Doig, Natalie Blair, Maria José Martin-Niclos, Erika Della Mina, Alejandro Rubio-Roldán, Jose L. García-Pérez, Duncan SproulJan Rehwinkel, Jonny Hertzog, Anne Boland-Auge, Robert Olaso, Jean-françois Deleuze, Julien Baruteau, Karine Brochard, Jonathan Buckley, Vanessa Cavallera, Cristina Cereda, Liesbeth M. H. De Waele, Angus Dobbie, Diane Doummar, Frances Elmslie, Margarete Koch-Hogrebe, Ram Kumar, Kate Lamb, John H. Livingston, Anirban Majumdar, Charles Marques Lorenço, Simona Orcesi, Sylviane Peudenier, Kevin Rostasy, Caroline A. Salmon, Christiaan Scott, Davide Tonduti, Guy Touati, Marialuisa Valente, Hélio Van Der Linden Jr, Hilde Van Esch, Marie Vermelle, Kate Webb, Andrew P. Jackson, Martin A. M. Reijns, Nick Gilbert, Yanick J. Crow

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi–Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA–processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS–stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.
Original languageEnglish
Pages (from-to)1364-1372
Number of pages9
JournalNature Genetics
Issue number12
Early online date23 Nov 2020
Publication statusPublished - 31 Dec 2020


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