In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators.
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.
1] Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller UniversityNew York New York 10065 USA [2].
Wen-Hui
WH
Lien
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller UniversityNew York New York 10065 USA.
Lisa
L
Polak
Department of Genetics, Albert Einstein College of MedicineBronx New York 10461 USA.
Mingyan
M
Lin
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller UniversityNew York New York 10065 USA.
Kenneth
K
Lay
1] Department of Genetics, Albert Einstein College of MedicineBronx New York 10461 USA [2] Department of Neurology, Albert Einstein College of MedicineBronx New York 10461 USA [3] Department of Neuroscience, Albert Einstein College of MedicineBronx New York 10461 USA.
Deyou
D
Zheng
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller UniversityNew York New York 10065 USA.
Elaine
E
Fuchs
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D018859:Hair Follicle / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012038:Regeneration; D015398:Signal Transduction; D000073940:Transcription Factor 4; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000502:physiology
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D000073940:Transcription Factor 4; D051153:Wnt Proteins; D051176:beta Catenin; C075668:Tcf3 protein, mouse; C090743:Tcf4 protein, mouse