Mechanical stress affects methylation pattern of GNAS isoforms and osteogenic differentiation of hAT-MSCs

Angeliki Maria Vlaikou, Dimitrios Kouroupis, Argyro Sgourou, Georgios S. Markopoulos, Eleni Bagli, Maria Markou, Zoe Papadopoulou, Theodore Fotsis, Georgios Nakos, Maria Eleni E. Lekka, Maria Syrrou

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Mechanical stress exerts a substantial role on skeletal-cell renewal systems, whereas accumulating evidence suggests that epigenetic mechanisms induce changes and differential gene expression. Although the underlying mechanisms remain to be fully elucidated, our study suggests that the influence of the long term mechanical stimulation elicits epigenetic modifications controlling osteogenic differentiation of human adipose tissue multipotential stromal cells (hAT-MSCs) and contributes to an accelerating in vitro osteogenesis. GNAS imprinting gene acts as a critical regulator of osteoblast differentiation and is implicated in human genetic disorders with pathological formation of ectopic-skeletal bone. Investigating a wide variety of stimuli, we showed that daily mechanical stretch on hAT-MSCs of 7th and 15th days' intervals induced a significant down-regulation in DNA methylation status of critical CpG sites of NESP and GNASXL isoforms, accompanied by up-regulation of the corresponding gene transcripts, and osteogenic differentiation earlier in culture. Importantly, methylation analysis of differentiating bone marrow-derived MSCs revealed similar methylation patterns. Bioinformatic analysis further showed that all CpG islands exhibiting significant methylation alterations encompassed transcriptional repressor CTCF binding sites. We hereby emphasize the need to investigate the epigenetic alterations on hAT-MSCs during environmental mechanical forces and to consider how the knowledge gained through these studies may foster new means of symptoms prevention and management of ectopic bone formation in the clinic.

Original languageEnglish (US)
Pages (from-to)1371-1381
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1864
Issue number8
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

Keywords

  • CTCF binding factors
  • Ectopic bone formation
  • GNAS isoforms
  • Mechanical stretching
  • Methylation profile
  • Osteogenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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