Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development

The role of heterochromatin in cell fate specification during development is unclear. We demonstrate that loss of the lysine 9 of histone H3 (H3K9) methyltransferase G9a in the mammary epithelium results in de novo chromatin opening, aberrant formation of the mammary ductal tree, impaired stem cell...

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Authors: Avgustinova, Alexandra, Laudanna, Carmelo, Pascual García, Mónica, Rovira, Quirze, Djurec, Magdolna, Castellanos, Andrés, Urdiroz Urricelqui, Uxue, Marchese, Domenica, Prats, Neus, Van Keymeulen, Alexandra, Heyn, Holger, Vaquerizas, Juan M., Aznar Benitah, Salvador
Format: article
Status:Versión aceptada para publicación
Publication Date:2021
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/178649
Online Access:https://hdl.handle.net/2445/178649
Access Level:Open access
Keyword:Retrovirus
Glàndules mamàries
Retroviruses
Mammary glands
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spelling Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland developmentAvgustinova, AlexandraLaudanna, CarmeloPascual García, MónicaRovira, QuirzeDjurec, MagdolnaCastellanos, AndrésUrdiroz Urricelqui, UxueMarchese, DomenicaPrats, NeusVan Keymeulen, AlexandraHeyn, HolgerVaquerizas, Juan M.Aznar Benitah, SalvadorRetrovirusGlàndules mamàriesRetrovirusesMammary glandsThe role of heterochromatin in cell fate specification during development is unclear. We demonstrate that loss of the lysine 9 of histone H3 (H3K9) methyltransferase G9a in the mammary epithelium results in de novo chromatin opening, aberrant formation of the mammary ductal tree, impaired stem cell potential, disrupted intraductal polarity, and loss of tissue function. G9a loss derepresses long terminal repeat (LTR) retroviral sequences (predominantly the ERVK family). Transcriptionally activated endogenous retroviruses generate double-stranded DNA (dsDNA) that triggers an antiviral innate immune response, and knockdown of the cytosolic dsDNA sensor Aim2 in G9a knockout (G9acKO) mammary epithelium rescues mammary ductal invasion. Mammary stem cell transplantation into immunocompromised or G9acKO-conditioned hosts shows partial dependence of the G9acKO mammary morphological defects on the inflammatory milieu of the host mammary fat pad. Thus, altering the chromatin accessibility of retroviral elements disrupts mammary gland development and stem cell activity through both cell-autonomous and non-autonomous mechanisms.Elsevier2021202220212021info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion24 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/178649Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1016/j.stem.2021.04.030Cell Stem Cell, 2021https://doi.org/10.1016/j.stem.2021.04.030cc by-nc-nd (c) Elsevier, 2021http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1786492026-05-29T05:05:01Z
dc.title.none.fl_str_mv Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development
title Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development
spellingShingle Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development
Avgustinova, Alexandra
Retrovirus
Glàndules mamàries
Retroviruses
Mammary glands
title_short Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development
title_full Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development
title_fullStr Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development
title_full_unstemmed Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development
title_sort Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development
dc.creator.none.fl_str_mv Avgustinova, Alexandra
Laudanna, Carmelo
Pascual García, Mónica
Rovira, Quirze
Djurec, Magdolna
Castellanos, Andrés
Urdiroz Urricelqui, Uxue
Marchese, Domenica
Prats, Neus
Van Keymeulen, Alexandra
Heyn, Holger
Vaquerizas, Juan M.
Aznar Benitah, Salvador
author Avgustinova, Alexandra
author_facet Avgustinova, Alexandra
Laudanna, Carmelo
Pascual García, Mónica
Rovira, Quirze
Djurec, Magdolna
Castellanos, Andrés
Urdiroz Urricelqui, Uxue
Marchese, Domenica
Prats, Neus
Van Keymeulen, Alexandra
Heyn, Holger
Vaquerizas, Juan M.
Aznar Benitah, Salvador
author_role author
author2 Laudanna, Carmelo
Pascual García, Mónica
Rovira, Quirze
Djurec, Magdolna
Castellanos, Andrés
Urdiroz Urricelqui, Uxue
Marchese, Domenica
Prats, Neus
Van Keymeulen, Alexandra
Heyn, Holger
Vaquerizas, Juan M.
Aznar Benitah, Salvador
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Retrovirus
Glàndules mamàries
Retroviruses
Mammary glands
topic Retrovirus
Glàndules mamàries
Retroviruses
Mammary glands
description The role of heterochromatin in cell fate specification during development is unclear. We demonstrate that loss of the lysine 9 of histone H3 (H3K9) methyltransferase G9a in the mammary epithelium results in de novo chromatin opening, aberrant formation of the mammary ductal tree, impaired stem cell potential, disrupted intraductal polarity, and loss of tissue function. G9a loss derepresses long terminal repeat (LTR) retroviral sequences (predominantly the ERVK family). Transcriptionally activated endogenous retroviruses generate double-stranded DNA (dsDNA) that triggers an antiviral innate immune response, and knockdown of the cytosolic dsDNA sensor Aim2 in G9a knockout (G9acKO) mammary epithelium rescues mammary ductal invasion. Mammary stem cell transplantation into immunocompromised or G9acKO-conditioned hosts shows partial dependence of the G9acKO mammary morphological defects on the inflammatory milieu of the host mammary fat pad. Thus, altering the chromatin accessibility of retroviral elements disrupts mammary gland development and stem cell activity through both cell-autonomous and non-autonomous mechanisms.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/178649
url https://hdl.handle.net/2445/178649
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1016/j.stem.2021.04.030
Cell Stem Cell, 2021
https://doi.org/10.1016/j.stem.2021.04.030
dc.rights.none.fl_str_mv cc by-nc-nd (c) Elsevier, 2021
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Elsevier, 2021
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 24 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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