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.

异染色质在发育过程中在细胞命运规范中的作用尚不清楚。我们证明了乳腺上皮中组蛋白 H3 (H3K9) 甲基转移酶 G9a 赖氨酸 9 的缺失导致从头染色质开放、乳腺导管树的异常形成、干细胞电位受损、导管内极性破坏和组织功能丧失。G9a 缺失去抑制长末端重复 (LTR) 逆转录病毒序列（主要是 ERVK 家族）。转录激活的内源性逆转录病毒产生双链 DNA (dsDNA)，触发抗病毒先天免疫反应，并敲除胞质 dsDNA 传感器Aim2在 G9a 基因敲除 (G9acKO) 中，乳腺上皮细胞挽救了乳腺导管的侵袭。将乳腺干细胞移植到免疫功能低下或 G9acKO 条件宿主中显示出 G9acKO 乳腺形态缺陷对宿主乳腺脂肪垫炎症环境的部分依赖性。因此，改变逆转录病毒元件的染色质可及性通过细胞自主和非自主机制破坏乳腺发育和干细胞活性。