Telomere dysfunction impairs epidermal stem cell specification and differentiation by disrupting BMP/pSmad/P63 signaling

PLoS Genet. 2019 Sep 13;15(9):e1008368. doi: 10.1371/journal.pgen.1008368. eCollection 2019 Sep.

Abstract

Telomere shortening is associated with aging and age-associated diseases. Additionally, telomere dysfunction resulting from telomerase gene mutation can lead to premature aging, such as apparent skin atrophy and hair loss. However, the molecular signaling linking telomere dysfunction to skin atrophy remains elusive. Here we show that dysfunctional telomere disrupts BMP/pSmad/P63 signaling, impairing epidermal stem cell specification and differentiation of skin and hair follicles. We find that telomere shortening mediated by Terc loss up-regulates Follistatin (Fst), inhibiting pSmad signaling and down-regulating P63 and epidermal keratins in an ESC differentiation model as well as in adult development of telomere-shortened mice. Mechanistically, short telomeres disrupt PRC2/H3K27me3-mediated repression of Fst. Our findings reveal that skin atrophy due to telomere dysfunction is caused by a previously unappreciated link with Fst and BMP signaling that could be explored in the development of therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrophy / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Cell Proliferation / genetics
  • Epidermal Cells / metabolism
  • Epidermis / metabolism
  • Gene Expression Regulation / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Signal Transduction / genetics
  • Smad Proteins / metabolism
  • Stem Cells / metabolism*
  • Telomere / genetics
  • Telomere Shortening / genetics
  • Telomere Shortening / physiology*
  • Trans-Activators / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Smad Proteins
  • Trans-Activators
  • Trp63 protein, mouse

Grant support

Lin Liu acknowledges funding from China MOST National Major Basic Research Program (2012CB911202), National Key R&D Program of China (2018YFA0107000), Program of International S&T Cooperation (2014DFA30450) and China Ministry of Education (PCSIRT IRT13023). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.