Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis

Nat Commun. 2019 Jul 26;10(1):3329. doi: 10.1038/s41467-019-10831-8.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cellular Senescence
  • Heterochromatin / genetics
  • Heterochromatin / metabolism*
  • Humans
  • Lamin Type B / genetics
  • Lamin Type B / metabolism
  • Male
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • MicroRNAs / genetics
  • Osteoarthritis / genetics
  • Osteoarthritis / metabolism*
  • Osteoarthritis / physiopathology
  • Protein Stability
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Tripartite Motif-Containing Protein 28 / genetics
  • Tripartite Motif-Containing Protein 28 / metabolism

Substances

  • DGCR8 protein, human
  • Dgcr8 protein, mouse
  • Heterochromatin
  • Lamin Type B
  • MicroRNAs
  • RNA-Binding Proteins
  • lamin B1
  • TRIM28 protein, human
  • Tripartite Motif-Containing Protein 28