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; 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, 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 (Academic Journal) › peer-review

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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-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
DOIs	https://doi.org/10.1038/s41588-020-00737-3
Publication status	Published - Dec 2020

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Bristol Neuromuscular Research Group

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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{d1e357dadc714bca9dea9aeb2dbe51bb,

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}, 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,

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

language = "English",

volume = "52",

pages = "1364--1372",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Springer Nature",

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-F, 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, 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, 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

Y1 - 2020/12

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 (Academic Journal)

C2 - 33230297

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

Abstract

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