Genome-wide analysis identifies differential promoter methylation of Leprel2, Foxf1, Mmp25, Igfbp6, and Peg12 in murine tendinopathy

J Orthop Res. 2017 May;35(5):947-955. doi: 10.1002/jor.23393. Epub 2016 Aug 29.


We have used a murine Achilles tendinopathy model to investigate whether tissue changes (such as collagen disorganization, chondroid metaplasia, and loss of tensile properties) which are broadly characteristic of human tendinopathies, are accompanied by changes in the expression of chromatin-modifying enzymes and the methylation status of promoter regions of tendon cell DNA. Tendinopathy was induced by two intra-tendinous TGF-β1 injections followed by cage activity or treadmill running for up to 28 days. Activation of DNA methyltransferases occurred at 3 days after the TGF-β1 injections and also at 14 days, but only with treadmill activity. Genome-wide Methyl Mini-Seq™ analysis identified 19 genes with differentially methylated promoters, five of which perform functions with an apparent direct relevance to tendinopathy (Leprel2, Foxf1, Mmp25, Igfbp6, and Peg12). The functions of the genes identified included collagen fiber assembly and pericellular interactions, therefore their perturbation could play a role in the characteristic disorganization of fibers in affected tendons. We postulate that a study of the functional genomics of these genes in animal and human tendon could further delineate the pathogenesis of this multi-factorial complex disease. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:947-955, 2017.

Keywords: chromatin-modifying enzymes; gene expression; methylome; promoter methylation; tendinopathy.

MeSH terms

  • Achilles Tendon / pathology
  • Animals
  • Carrier Proteins / genetics
  • DNA Methylation*
  • Disease Models, Animal
  • Forkhead Transcription Factors / genetics
  • GPI-Linked Proteins / genetics
  • Gene Expression
  • Genome-Wide Association Study
  • Male
  • Matrix Metalloproteinases, Membrane-Associated / genetics
  • Mice, Inbred C57BL
  • Neoplasm Proteins / genetics
  • Procollagen-Proline Dioxygenase / genetics
  • Promoter Regions, Genetic
  • Tendinopathy / metabolism*
  • Tendinopathy / pathology


  • Carrier Proteins
  • Forkhead Transcription Factors
  • Foxf1 protein, mouse
  • GPI-Linked Proteins
  • Neoplasm Proteins
  • Peg12 protein, mouse
  • Procollagen-Proline Dioxygenase
  • LEPREL1 protein, mouse
  • Matrix Metalloproteinases, Membrane-Associated
  • matrix metalloproteinase 25