TY - JOUR
T1 - In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators
AU - Lien, Wen Hui
AU - Polak, Lisa
AU - Lin, Mingyan
AU - Lay, Kenneth
AU - Zheng, Deyou
AU - Fuchs, Elaine
N1 - Funding Information:
We thank S. Dewell for assistance in high-throughput sequencing (RU Genomics Resource Center), X. Guo for help in ChIP-seq analysis (Zheng laboratory), and S. Mazel, L. Li, S. Semova and S. Tadesse for FACS sorting (RU FACS facility). We also thank Fuchs’ laboratory members N. Stokes, D. Oristian and A. Aldeguer for assistance in mouse research (Fuchs laboratory); A. Rodriguez-Folgueras for assistance in confocal microscopy; and T. Chen, A. Rodriguez-Folgueras, S. Luo and B. Keyes for discussions and comments. W-H.L. was supported by a Harvey L. Karp Postdoctoral Fellowship and a Jane Coffin Child Fellowship. E.F. is an HHMI Investigator. This work was supported by a grant (to E.F.) from the NIH/NIAMS (R01AR31737) and partially by NIH/NIMH (R21MH099452, R01MH073164, D.Z.).
PY - 2014/2
Y1 - 2014/2
N2 - Hair follicle stem cells (HFSCs) regenerate hair in response to Wnt signalling. Here, we unfold genome-wide transcriptional and chromatin landscapes of β-catenin-TCF3/4-TLE circuitry, and genetically dissect their biological roles within the native HFSC niche. We show that during HFSC quiescence, TCF3, TCF4 and TLE (Groucho) bind coordinately and transcriptionally repress Wnt target genes. We also show that β-catenin is dispensable for HFSC viability, and if TCF3/4 levels are sufficiently reduced, it is dispensable for proliferation. However, β-catenin is essential to activate genes that launch hair follicle fate and suppress sebocyte fate determination. TCF3/4 deficiency mimics Wnt-β-catenin-dependent activation of these hair follicle fate targets; TCF3 overexpression parallels their TLE4-dependent suppression. Our studies unveil TCF3/4-TLE histone deacetylases as a repressive rheostat, whose action can be relieved by Wnt-β-catenin signalling. When TCF3/4 and TLE levels are high, HFSCs can maintain stemness, but remain quiescent. When these levels drop or when Wnt-β-catenin levels rise, this balance is shifted and hair regeneration initiates.
AB - Hair follicle stem cells (HFSCs) regenerate hair in response to Wnt signalling. Here, we unfold genome-wide transcriptional and chromatin landscapes of β-catenin-TCF3/4-TLE circuitry, and genetically dissect their biological roles within the native HFSC niche. We show that during HFSC quiescence, TCF3, TCF4 and TLE (Groucho) bind coordinately and transcriptionally repress Wnt target genes. We also show that β-catenin is dispensable for HFSC viability, and if TCF3/4 levels are sufficiently reduced, it is dispensable for proliferation. However, β-catenin is essential to activate genes that launch hair follicle fate and suppress sebocyte fate determination. TCF3/4 deficiency mimics Wnt-β-catenin-dependent activation of these hair follicle fate targets; TCF3 overexpression parallels their TLE4-dependent suppression. Our studies unveil TCF3/4-TLE histone deacetylases as a repressive rheostat, whose action can be relieved by Wnt-β-catenin signalling. When TCF3/4 and TLE levels are high, HFSCs can maintain stemness, but remain quiescent. When these levels drop or when Wnt-β-catenin levels rise, this balance is shifted and hair regeneration initiates.
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U2 - 10.1038/ncb2903
DO - 10.1038/ncb2903
M3 - Article
C2 - 24463605
AN - SCOPUS:84895910257
SN - 1465-7392
VL - 16
SP - 179
EP - 190
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 2
ER -