Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis.,Nature Communications

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Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis.
Nature Communications ( IF 14.7 ) Pub Date : 2019-07-26 , DOI: 10.1038/s41467-019-10831-8
Liping Deng _{1,

2,

3,

4} , Ruotong Ren ₁ , Zunpeng Liu _{2,

4} , Moshi Song _{3,

4,

5} , Jingyi Li _{1,

6} , Zeming Wu _{2,

4} , Xiaoqing Ren _{1,

4} , Lina Fu _{1,

4} , Wei Li ₆ , Weiqi Zhang _{1,

4,

5,

6,

7} , Pedro Guillen ₈ , Juan Carlos Izpisua Belmonte ₉ , Piu Chan ₆ , Jing Qu _{2,

4,

5} , Guang-Hui Liu _{1,

4,

5,

6,

10,

11}

Affiliation

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.
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China.
University of Chinese Academy of Sciences, 100049, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, China.
Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, 100053, Beijing, China.
Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, 100101, Beijing, China.
Clinica Cemtro. Av. del Ventisquero de la Condesa, 42, 28035, Madrid, Spain.
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, 510632, Guangzhou, China.
Beijing Institute for Brain Disorders, Capital Medical University, 100069, Beijing, China.

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 DR8dex2 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.

中文翻译：

DGCR8 稳定异染色质可缓解衰老和骨关节炎。

DiGeorge 综合征关键区 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 的非规范功能尚未被研究。在这里，我们证明 DGCR8 在维持异染色质组织和延缓衰老方面发挥着重要作用。 DGCR8 (DR8dex2) 的 N 端截短版本可加速人间充质干细胞 (hMSC) 的衰老，而与其 microRNA 加工活性无关。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。任何这些蛋白质（包括 DGCR8）的过度表达，都能逆转 DR8dex2 hMSC 中的过早衰老表型。最后，DGCR8 在病理和自然老化的 hMSC 中下调，而 DGCR8 过表达则减轻 hMSC 老化和小鼠骨关节炎。总而言之，这些分析揭示了 DGCR8 在维持异染色质组织和减轻衰老方面具有新颖的、独立于 microRNA 加工的作用，从而代表了缓解人类衰老相关疾病的新治疗靶点。

更新日期：2019-07-26

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