Long non-coding RNA GRASLND enhances chondrogenesis via suppression of the interferon type II signaling pathway

Elife. 2020 Mar 23;9:e49558. doi: 10.7554/eLife.49558.

Abstract

The roles of long noncoding RNAs (lncRNAs) in musculoskeletal development, disease, and regeneration remain poorly understood. Here, we identified the novel lncRNA GRASLND (originally named RNF144A-AS1) as a regulator of mesenchymal stem cell (MSC) chondrogenesis. GRASLND, a primate-specific lncRNA, is upregulated during MSC chondrogenesis and appears to act directly downstream of SOX9, but not TGF-β3. We showed that the silencing of GRASLND resulted in lower accumulation of cartilage-like extracellular matrix in a pellet assay, while GRASLND overexpression - either via transgene ectopic expression or by endogenous activation via CRISPR-dCas9-VP64 - significantly enhanced cartilage matrix production. GRASLND acts to inhibit IFN-γ by binding to EIF2AK2, and we further demonstrated that GRASLND exhibits a protective effect in engineered cartilage against interferon type II. Our results indicate an important role of GRASLND in regulating stem cell chondrogenesis, as well as its therapeutic potential in the treatment of cartilage-related diseases, such as osteoarthritis.

Keywords: RNF144A-AS1; human; mesenchymal stem cells; regenerative medicine; stem cells; tissue engineering.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Chondrocytes / cytology
  • Chondrogenesis / genetics*
  • Extracellular Matrix / metabolism
  • Gene Editing
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Gene Regulatory Networks
  • Humans
  • Immunohistochemistry
  • Interferon-gamma / metabolism*
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Protein Binding
  • RNA, Long Noncoding / genetics*
  • Signal Transduction*

Substances

  • RNA, Long Noncoding
  • Interferon-gamma

Associated data

  • GEO/GSE129985
  • GEO/GSE109503
  • GEO/GSE69110
  • GEO/GSE57218