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

• Published in: Cell stem cell 2021-10, Vol.28 (10), p.1790-1804.e8
• Main Authors: Avgustinova, Alexandra, Laudanna, Carmelo, Pascual-García, Mónica, Rovira, Quirze, Djurec, Magdolna, Castellanos, Andres, Urdiroz-Urricelqui, Uxue, Marchese, Domenica, Prats, Neus, Van Keymeulen, Alexandra, Heyn, Holger, Vaquerizas, Juan M., Benitah, Salvador Aznar
• Format: Article
• Language: English
• Subjects: Adipose Tissue - growth & development; Adipose Tissue - immunology; Animals; chromatin accessibility; endogenous retroviruses; Endogenous Retroviruses - genetics; Endogenous Retroviruses - metabolism; epigenomics; Female; G9a/GLP; Histone-Lysine N-Methyltransferase - metabolism; Histones - metabolism; Immunity; mammary gland development; Mammary Glands, Animal - growth & development; Mammary Glands, Animal - immunology; pyroptosis; single cell genomics; stem cells
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2021.04.030

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. [Display omitted] •Impaired mammary gland development upon loss of H3K9 methyltransferase G9a•G9a loss opens chromatin in regions harboring endogenous retroviruses•Expression of endogenous retroviruses triggers cellular antiviral response•Inhibition of cell’s antiviral response ameliorates the observed mammary gland defects The role of chromatin accessibility in tissue development is not well understood. Avgustinova and colleagues demonstrate that increased chromatin accessibility results in delayed and aberrant mammary gland development. These defects are partially cell autonomous and in part caused by an altered mammary milieu following transcriptional derepression of endogenous retroviruses.