Setdb1 protects genome integrity in murine muscle stem cells to allow for regenerative myogenesis and inflammation,Developmental Cell

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Setdb1 protects genome integrity in murine muscle stem cells to allow for regenerative myogenesis and inflammation
Developmental Cell ( IF 10.7 ) Pub Date : 2024-06-06 , DOI: 10.1016/j.devcel.2024.05.012
Pauline Garcia ₁ , William Jarassier ₁ , Caroline Brun ₁ , Lorenzo Giordani ₂ , Fany Agostini ₁ , Wai Hing Kung ₃ , Cécile Peccate ₂ , Jade Ravent ₁ , Sidy Fall ₁ , Valentin Petit ₄ , Tom H Cheung ₃ , Slimane Ait-Si-Ali ₄ , Fabien Le Grand ₁

Affiliation

The histone H3 lysine 9 methyltransferase SETDB1 controls transcriptional repression to direct stem cell fate. Here, we show that Setdb1 expression by adult muscle stem cells (MuSCs) is required for skeletal muscle regeneration. We find that SETDB1 represses the expression of endogenous retroviruses (ERVs) in MuSCs. ERV de-repression in MuSCs prevents their amplification following exit from quiescence and promotes cell death. Multi-omics profiling shows that chromatin decompaction at ERV loci activates the DNA-sensing cGAS-STING pathway, entailing cytokine expression by MuSCs. This is followed by aberrant infiltration of inflammatory cells, including pathological macrophages. The ensuing histiocytosis is accompanied by myofiber necrosis, which, in addition to progressive MuSCs depletion, completely abolishes tissue repair. In contrast, loss of in fibro-adipogenic progenitors (FAPs) does not impact immune cells. In conclusion, genome maintenance by SETDB1 in an adult somatic stem cell is necessary for both its regenerative potential and adequate reparative inflammation.

中文翻译：

Setdb1 保护小鼠肌肉干细胞中的基因组完整性，以实现再生肌生成和炎症

组蛋白 H3 赖氨酸 9 甲基转移酶 SETDB1 控制转录抑制以指导干细胞的命运。在这里，我们证明成体肌肉干细胞 (MuSC) 表达 Setdb1 是骨骼肌再生所必需的。我们发现 SETDB1 抑制 MuSC 中内源性逆转录病毒 (ERV) 的表达。 MuSC 中的 ERV 去抑制可防止其在退出静止状态后扩增并促进细胞死亡。多组学分析表明，ERV 位点的染色质解压缩激活 DNA 感应 cGAS-STING 通路，从而导致 MuSC 表达细胞因子。随后是炎症细胞的异常浸润，包括病理性巨噬细胞。随之而来的组织细胞增多症伴随着肌纤维坏死，除了逐渐消耗 MuSC 之外，还完全破坏了组织修复。相比之下，纤维脂肪祖细胞（FAP）的丢失不会影响免疫细胞。总之，成体干细胞中 SETDB1 的基因组维护对于其再生潜力和充分的修复性炎症是必要的。

更新日期：2024-06-06

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