In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regul

[IDW2BB]

Fuchs may not give a crap about us baldies but she is reverse engineering everything having to do with the hair follicle so I can't hate her!





http://www.ncbi.nlm.nih.gov/pubmed/24463605

Abstract

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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I know we aren't supposed to link other studies but I want to make a connection. Sorry


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299836/

Conversion of the Wnt transcription factor TCF/Lef from a transcriptional repressor to an activator is a critical event in Wnt signal transduction, yet our understanding as to how this switch occurs in cells is limited. The current model, based primarily on reconstitution studies using purified proteins, proposes direct displacement of the transcriptional co-repressor Gro/TLE by the co-activator β-catenin through competition for overlapping binding sites on TCF/Lef (Daniels and Weis).

Our data suggest a model (Figure 7) in which XIAP constitutively binds and ubiquitylates non-TCF-bound Gro/TLE in the nucleus, thereby limiting the amount of Gro/TLE available to form co-repressor complexes with TCF/Lef. In the presence of a Wnt signal, XIAP is recruited to TCF/Lef transcriptional complexes where it promotes dissociation of Gro/TLE. Our experiments were not able to distinguish whether XIAP ubiquitylates Gro/TLE bound to TCF/Lef to promote its dissociation or ubiquitylates dissociated Gro/TLE, thereby blocking its re-association. Regardless, ubiquitylation of Gro/TLE by TCF/Lef-bound XIAP further decreases the affinity of Gro/TLE for TCF/Lef, thereby allowing efficient recruitment and binding of the transcriptional co-activator β-catenin to TCF/Lef that is required to initiate a Wnt-specific transcriptional program. The mechanism by which XIAP is recruited to TCF/Lef transcriptional complexes is unknown, although our results demonstrating that lithium can also induce recruitment of XIAP to TCF/Lef suggest that GSK3 activity plays an important role in regulating this process.