Journal Article

Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis

Ren, Ruotong, Izpisua Belmonte, Juan Carlos, Qu, Jing, Li, Jingyi, Chan, Piu, Li, Wei, Guillen, Pedro, Liu, Zunpeng, Zhang, Weiqi, Ren, Xiaoqing, Deng, Liping, Song, Moshi, Fu, Lina, Liu, Guang-Hui, Wu, Zeming

2019

Overview

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 dex2 ) 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 dex2 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 is a component of the canonical microprocessor complex for microRNA biogenesis. Here the authors implicate DGCR8 in heterochromatin maintenance and aging attenuation independent of its miRNA-processing activity through Lamin B1, KAP1 and HP1 interaction. DGCR8 overexpression can alleviate aging and senescence

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/15 / 631/337/100/102 / 631/532/489 / 631/532/7 / 631/80/509 / Age related diseases / Aging / Animals / Arthritis / Biocompatibility / Cellular Senescence / Critical components / Heterochromatin / Heterochromatin - genetics / Heterochromatin - metabolism / Humanities and Social Sciences / Humans / Lamin Type B - genetics / Lamin Type B - metabolism / Male / Mesenchymal Stem Cells - metabolism / Mesenchyme / Mice / Mice, Inbred C57BL / Mice, Inbred NOD / MicroRNAs / MicroRNAs - genetics / miRNA / multidisciplinary / Osteoarthritis / Osteoarthritis - genetics / Osteoarthritis - metabolism / Osteoarthritis - physiopathology / Phenotypes / Protein Stability / Proteins / Ribonucleic acid / RNA / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Science / Science (multidisciplinary) / Senescence / Stem cell transplantation / Stem cells / Therapeutic applications / Thymic hypoplasia / Tripartite Motif-Containing Protein 28 - genetics / Tripartite Motif-Containing Protein 28 - metabolism / Viral envelope proteins