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 Sproul; Jan 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

doi:10.1038/s41588-020-00737-3

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 journal › Article › peer-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 language	English
Pages (from-to)	1364-1372
Number of pages	9
Journal	Nature Genetics
Volume	52
Issue number	12
Early online date	23 Nov 2020
DOIs	https://doi.org/10.1038/s41588-020-00737-3
Publication status	Published - 31 Dec 2020

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MC_UU_00007/5 From Microcephaly to Genome Stability, Inflammation and Growth Regulation
Jackson, A.
1/04/18 → 31/03/23
Project: Research
Chromatin architecture and regulation
Gilbert, N.
1/04/18 → 31/03/23
Project: Research

Advanced Imaging Resource
Ann Wheeler (Manager), Laura Murphy (Other), Martin Lee (Other), Helen Caldwell (Other), Matthew Pearson (Other) & James Iremonger (Other)
Deanery of Molecular, Genetic and Population Health Sciences
Facility/equipment: Facility

Yanick Crow
- Deanery of Molecular, Genetic and Population Health Sciences - Chair of Genomic Medicine
- Centre for Genomic and Experimental Medicine
- Edinburgh Neuroscience
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Uggenti, C., Lepelley, A., Depp, M., Badrock, A. P., Rodero, M. P., El-Daher, M.-T., Rice, G. I., Dhir, S., Wheeler, A. P., Dhir, A., Albawardi, W., Frémond, M.-L., Seabra, L., Doig, J., Blair, N., Martin-Niclos, M. J., Della Mina, E., Rubio-Roldán, A., García-Pérez, J. L., ... Crow, Y. J. (2020). cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing. Nature Genetics, 52(12), 1364-1372. https://doi.org/10.1038/s41588-020-00737-3

@article{e16b5cf69d6240d9946372cbed274985,

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

abstract = "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–Gouti{\`e}res 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.",

author = "Carolina Uggenti and Alice Lepelley and Marine Depp and Badrock, {Andrew P.} and Rodero, {Mathieu P.} and Marie-Th{\'e}r{\`e}se El-Daher and Rice, {Gillian I.} and Somdutta Dhir and Wheeler, {Ann P.} and Ashish Dhir and Waad Albawardi and Marie-Louise Fr{\'e}mond and Luis Seabra and Jennifer Doig and Natalie Blair and Martin-Niclos, {Maria Jos{\'e}} and {Della Mina}, Erika and Alejandro Rubio-Rold{\'a}n and Garc{\'i}a-P{\'e}rez, {Jose L.} and Duncan Sproul and Jan Rehwinkel and Jonny Hertzog and Anne Boland-Auge and Robert Olaso and Jean-fran{\c c}ois Deleuze and Julien Baruteau and Karine Brochard and Jonathan Buckley and Vanessa Cavallera and Cristina Cereda and {De Waele}, {Liesbeth M. H.} and Angus Dobbie and Diane Doummar and Frances Elmslie and Margarete Koch-Hogrebe and Ram Kumar and Kate Lamb and Livingston, {John H.} and Anirban Majumdar and Loren{\c c}o, {Charles Marques} and Simona Orcesi and Sylviane Peudenier and Kevin Rostasy and Salmon, {Caroline A.} and Christiaan Scott and Davide Tonduti and Guy Touati and Marialuisa Valente and {Van Der Linden Jr}, H{\'e}lio and {Van Esch}, Hilde and Marie Vermelle and Kate Webb and Jackson, {Andrew P.} and Reijns, {Martin A. M.} and Nick Gilbert and Crow, {Yanick J.}",

year = "2020",

month = dec,

day = "31",

doi = "10.1038/s41588-020-00737-3",

language = "English",

volume = "52",

pages = "1364--1372",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

}

Uggenti, C, Lepelley, A, Depp, M, Badrock, AP, Rodero, MP, El-Daher, M-T, Rice, GI, Dhir, S, Wheeler, AP, Dhir, A, Albawardi, W, Frémond, M-L, Seabra, L, Doig, J, Blair, N, Martin-Niclos, MJ, Della Mina, E, Rubio-Roldán, A, García-Pérez, JL, Sproul, D, Rehwinkel, J, Hertzog, J, Boland-Auge, A, Olaso, R, Deleuze, J, Baruteau, J, Brochard, K, Buckley, J, Cavallera, V, Cereda, C, De Waele, LMH, Dobbie, A, Doummar, D, Elmslie, F, Koch-Hogrebe, M, Kumar, R, Lamb, K, Livingston, JH, Majumdar, A, Lorenço, CM, Orcesi, S, Peudenier, S, Rostasy, K, Salmon, CA, Scott, C, Tonduti, D, Touati, G, Valente, M, Van Der Linden Jr, H, Van Esch, H, Vermelle, M, Webb, K, Jackson, AP , Reijns, MAM , Gilbert, N & Crow, YJ 2020, 'cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing', Nature Genetics, vol. 52, no. 12, pp. 1364-1372. https://doi.org/10.1038/s41588-020-00737-3

TY - JOUR

T1 - cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing

AU - Uggenti, Carolina

AU - Lepelley, Alice

AU - Depp, Marine

AU - Badrock, Andrew P.

AU - Rodero, Mathieu P.

AU - El-Daher, Marie-Thérèse

AU - Rice, Gillian I.

AU - Dhir, Somdutta

AU - Wheeler, Ann P.

AU - Dhir, Ashish

AU - Albawardi, Waad

AU - Frémond, Marie-Louise

AU - Seabra, Luis

AU - Doig, Jennifer

AU - Blair, Natalie

AU - Martin-Niclos, Maria José

AU - Della Mina, Erika

AU - Rubio-Roldán, Alejandro

AU - García-Pérez, Jose L.

AU - Sproul, Duncan

AU - Rehwinkel, Jan

AU - Hertzog, Jonny

AU - Boland-Auge, Anne

AU - Olaso, Robert

AU - Deleuze, Jean-françois

AU - Baruteau, Julien

AU - Brochard, Karine

AU - Buckley, Jonathan

AU - Cavallera, Vanessa

AU - Cereda, Cristina

AU - De Waele, Liesbeth M. H.

AU - Dobbie, Angus

AU - Doummar, Diane

AU - Elmslie, Frances

AU - Koch-Hogrebe, Margarete

AU - Kumar, Ram

AU - Lamb, Kate

AU - Livingston, John H.

AU - Majumdar, Anirban

AU - Lorenço, Charles Marques

AU - Orcesi, Simona

AU - Peudenier, Sylviane

AU - Rostasy, Kevin

AU - Salmon, Caroline A.

AU - Scott, Christiaan

AU - Tonduti, Davide

AU - Touati, Guy

AU - Valente, Marialuisa

AU - Van Der Linden Jr, Hélio

AU - Van Esch, Hilde

AU - Vermelle, Marie

AU - Webb, Kate

AU - Jackson, Andrew P.

AU - Reijns, Martin A. M.

AU - Gilbert, Nick

AU - Crow, Yanick J.

PY - 2020/12/31

Y1 - 2020/12/31

N2 - 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.

AB - 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.

U2 - 10.1038/s41588-020-00737-3

DO - 10.1038/s41588-020-00737-3

M3 - Article

SN - 1061-4036

VL - 52

SP - 1364

EP - 1372

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

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

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MC_UU_00007/5 From Microcephaly to Genome Stability, Inflammation and Growth Regulation

Chromatin architecture and regulation

Equipment

Advanced Imaging Resource

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Yanick Crow

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