National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China.
Nat Commun. 2019 Jul 26;10(1):3329. doi: 10.1038/s41467-019-10831-8.
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 (DR8) 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 DR8 hMSCs. 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.
DGCR8（DiGeorge 综合征关键区域 8）是经典 microRNA 生物发生的微处理器复合物的关键组成部分。然而，DGCR8 的非经典功能尚未被研究。在这里，我们证明 DGCR8 在维持异染色质组织和减缓衰老方面起着重要作用。DGCR8 的 N 端截断版本（DR8）独立于其 microRNA 处理活性，加速了人类间充质干细胞（hMSCs）的衰老。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组织。这些蛋白中的任何一种（包括 DGCR8）的过表达都能逆转 DR8 hMSCs 中的过早衰老表型。最后，DGCR8 在病理性和自然衰老的 hMSCs 中下调，而 DGCR8 的过表达缓解了 hMSC 衰老和小鼠骨关节炎。综上所述，这些分析揭示了 DGCR8 在维持异染色质组织和减缓衰老方面的一种新的、与 microRNA 处理无关的作用，因此代表了一种缓解与人类衰老相关疾病的新的治疗靶点。
