Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis
Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis
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DGCR8 稳定异染色质可缓解衰老和骨关节炎
DOI：
10.1038/s41467-019-10831-8
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发表时间：
2019-07-26
影响因子：
16.6
通讯作者：
Liu, Guang-Hui
中科院分区：
文献类型：
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作者：
Deng, Liping;Ren, Ruotong;Liu, Guang-Hui
DiGeorge综合征临界区8(Dgcr8)是microRNA生物发生的典型微处理器复合体的关键组成部分。然而，Dgcr8的非正则功能尚未被研究。在这里，我们证明了Dgcr8在维持异染色质组织和延缓衰老方面发挥了重要作用。一个N端截短的Dgcr8(DR8dex2)可以加速人骨髓间充质干细胞(HMSCs)的衰老，而不依赖于它的microRNA处理活性。进一步的研究表明，Dgcr8通过与核膜蛋白Lamin B1以及异染色质相关蛋白KAP1和Hp1γ相互作用来维持异染色质的组织。其中任何一种蛋白的过表达，包括Dgcr8，都可以逆转DR8dex2hMSCs的早衰表型。最后，在病理和自然老化的hMSCs中，Dgcr8的表达下调，而Dgcr8的过表达减轻了hMSC的衰老和小鼠的骨关节炎。综上所述，这些分析揭示了Dgcr8在维持异染色质组织和延缓衰老方面的新的、不依赖于microRNA加工的作用，从而代表了缓解人类衰老相关疾病的新的治疗靶点。
DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and attenuating aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its microRNA-processing activity. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1γ. Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2hMSCs. Finally, DGCR8 was downregulated in pathologically and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and mouse osteoarthritis. Taken together, these analyses uncovered a novel, microRNA processing-independent role in maintaining heterochromatin organization and attenuating senescence by DGCR8, thus representing a new therapeutic target for alleviating human aging-related disorders.