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

Na Liu; Yu Yin; Haiying Wang; Zhongcheng Zhou; Xiaoyan Sheng; Haifeng Fu; Renpeng Guo; Hua Wang; Jiao Yang; Peng Gong; Wen Ning; Zhenyu Ju; Yifei Liu; Lin Liu

doi:10.1371/journal.pgen.1008368

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.

Authors

Na Liu^{1

2

3}, Yu Yin^{1

4}, Haiying Wang¹, Zhongcheng Zhou¹, Xiaoyan Sheng¹, Haifeng Fu¹, Renpeng Guo¹, Hua Wang¹, Jiao Yang¹, Peng Gong¹, Wen Ning¹, Zhenyu Ju⁵, Yifei Liu⁶, Lin Liu^{1

2}

Affiliations

¹ State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
² Key Laboratory of Bioactive Materials, Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, China.
³ School of Medicine, Nankai University, Tianjin, China.
⁴ Yunnan Key Laboratory of Primate Biomedical Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China.
⁵ Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China.
⁶ Yale Fertility Center and Department of OB/GYN, Yale University School of Medicine, New Haven, CT, United States of America.

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

Grants and funding

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.