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.
Highlights
Telomeres consist of (TTAGGG)n DNA repeats and associated proteins that locate at chromosome ends, maintaining chromosomal stability and cell proliferation
Short telomere impairs epidermal stem cell specification and differentiation in vitro To investigate the differentiation defects associated with short telomeres, we initially performed in vitro differentiation experiments by standard embryoid body (EB) formation test using mouse Embryonic stem (ES) cells with various telomere lengths due to telomerase (Terc–/–) deficiency (Fig 1A and 1B, S1A Fig)
Telomeres were longest in wild-type (WT) ES cells, shorter in heterozygous (Terc+/–) and early generation (G1) Terc knockout (Terc–/–)ES cells, and critically short or lost in late generation (G3 and G4) Terc–/–ES cells (Fig 1C and 1D), as we previously reported [17]
Summary
Telomeres consist of (TTAGGG)n DNA repeats and associated proteins that locate at chromosome ends, maintaining chromosomal stability and cell proliferation. The telomerase complex consists of a telomerase RNA component (TERC) and the reverse transcriptase catalytic subunit (TERT), and adds telomere repeats to chromosome ends to offset the loss of telomere sequences that occurs due to the end-replication problem, the inability of DNA polymerase to replicate fully the lagging DNA strand [1]. It has been shown that short telomeres impair differentiation and development of the epidermis, and cause skin atrophy and loss of hair follicles, in association with epidermal stem cell dysfunction with aging [8,9,10]. The molecular signaling underlying short telomeres-associated skin atrophy or degeneration and hair follicle loss remains elusive
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
