Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development
Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development
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DOI：
10.1016/j.stem.2021.04.030
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发表时间：
2021-10-07
期刊：
影响因子：
23.9
通讯作者：
Benitah, Salvador Aznar
中科院分区：
文献类型：
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作者：
Avgustinova, Alexandra;Laudanna, Carmelo;Benitah, Salvador Aznar
异染色质在细胞发育过程中决定细胞命运的作用尚不清楚。我们证明，组蛋白H3(H3K9)甲基转移酶G9a的赖氨酸9在乳腺上皮细胞中的缺失导致从头开始的染色质开放、乳腺导管树的异常形成、干细胞潜能受损、导管内极性的破坏和组织功能的丧失。G9a缺失降低了长末端重复(LTR)逆转录病毒序列(主要是ERVK家族)的表达。转录激活的内源性逆转录病毒产生双链DNA(DsDNA)，触发抗病毒的先天性免疫反应，而G9a基因敲除(G9acKO)乳腺上皮细胞内dsDNA传感器AIM2的敲除拯救了乳腺导管的侵袭。将乳腺干细胞移植到免疫低下或G9acKO条件下的宿主体内，表明G9acKO乳腺形态缺陷部分依赖于宿主乳腺脂肪垫的炎症环境。因此，改变逆转录病毒元件的染色质可及性会通过细胞自主和非自主机制扰乱乳腺发育和干细胞活动。
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.