Progenitor-derived endothelin controls dermal sheath contraction for hair follicle regression.

Substantial follicle remodelling during the regression phase of the hair growth cycle is coordinated by the contraction of the dermal sheath smooth muscle, but how dermal-sheath-generated forces are regulated is unclear. Here, we identify spatiotemporally controlled endothelin signalling-a potent vasoconstriction-regulating pathway-as the key activating mechanism of dermal sheath contraction. Pharmacological blocking or genetic ablation of both endothelin receptors, ETA and ETB, impedes dermal sheath contraction and halts follicle regression. Epithelial progenitors at the club hair-epithelial strand bottleneck produce the endothelin ligand ET-1, which is required for follicle regression. ET signalling in dermal sheath cells and downstream contraction is dynamically regulated by cytoplasmic Ca2+ levels through cell membrane and sarcoplasmic reticulum calcium channels. Together, these findings illuminate an epithelial-mesenchymal interaction paradigm in which progenitors-destined to undergo programmed cell death-control the contraction of the surrounding sheath smooth muscle to orchestrate homeostatic tissue regression and reorganization for the next stem cell activation and regeneration cycle.

The dermal sheath: An emerging component of the hair follicle stem cell niche.

Hair follicles cyclically regenerate throughout adult mammalian life, owing to a resident population of epithelial hair follicle stem cells. Stem cell (SC) activity drives bouts of follicle growth, which are periodically interrupted by follicle regression and rest. These phases and the transitions between them are tightly spatiotemporally coordinated by signalling crosstalk between stem/progenitor cells and the various cell types of the microenvironment, or niche. The dermal papilla (DP) is a cluster of specialized mesenchymal cells that have long been recognized for important niche roles in regulating hair follicle SC activation, as well as progenitor proliferation and differentiation during follicle growth. In addition to the DP, the mesenchyme of the murine pelage follicle is also comprised of a follicle-lining smooth muscle known as the dermal sheath (DS), which has been far less studied than the DP yet may be equally specialized and important for hair cycling. In this review, we define the murine pelage DS in comparison with human DS and discuss recent work that highlights the emergent importance of the DS in the hair follicle SC niche. Last, we examine potential therapeutic applications for the DS in hair regeneration and wound healing.

Cutting Edge: CRISPR-Based Transcriptional Regulators Reveal Transcription-Dependent Establishment of Epigenetic Memory of Foxp3 in Regulatory T Cells.

Transcription factor Foxp3 specifies and maintains regulatory T cell (Treg) identity. During Treg differentiation, a CpG-rich Foxp3 intronic enhancer, conserved noncoding sequence 2 (CNS2), is activated via DNA demethylation to establish epigenetic memory of Foxp3 expression to protect Treg identity. However, it is unclear how this epigenetic memory of Foxp3 expression is established, as CNS2 is thought to be demethylated independently of Foxp3 expression. In this article, we uncover an unexpected causal relationship between Foxp3-transcriptional activation and CNS2 demethylation in mice. CRISPR/dCas9-mediated Foxp3-transcriptional activation elicits CNS2 demethylation. Sustaining Foxp3-transcriptional activation in induced Tregs also promotes CNS2 demethylation, enhancing Treg lineage stability and suppressive function. Importantly, CRISPR-mediated silencing of Foxp3 transcription, but not protein expression, abolishes CNS2 demethylation. The novel finding that Foxp3-transcriptional activation promotes CNS2 demethylation may facilitate the development of Treg-based therapies and represent a general mechanism for the establishment of epigenetic memory of immune gene expression.

Dermal sheath contraction powers stem cell niche relocation during hair cycle regression.

Tissue homeostasis requires the balance of growth by cell production and regression through cell loss. In the hair cycle, during follicle regression, the niche traverses the skin through an unknown mechanism to reach the stem cell reservoir and trigger new growth. Here, we identify the dermal sheath that lines the follicle as the key driver of tissue regression and niche relocation through the smooth muscle contractile machinery that generates centripetal constriction force. We reveal that the calcium-calmodulin-myosin light chain kinase pathway controls sheath contraction. When this pathway is blocked, sheath contraction is inhibited, impeding follicle regression and niche relocation. Thus, our study identifies the dermal sheath as smooth muscle that drives follicle regression for reuniting niche and stem cells in order to regenerate tissue structure during homeostasis.

The Capacity to Act in Trans Varies Among Drosophila Enhancers.

The interphase nucleus is organized such that genomic segments interact in cis, on the same chromosome, and in trans, between different chromosomes. In Drosophila and other Dipterans, extensive interactions are observed between homologous chromosomes, which can permit enhancers and promoters to communicate in trans Enhancer action in trans has been observed for a handful of genes in Drosophila, but it is as yet unclear whether this is a general property of all enhancers or specific to a few. Here, we test a collection of well-characterized enhancers for the capacity to act in trans Specifically, we tested 18 enhancers that are active in either the eye or wing disc of third instar Drosophila larvae and, using two different assays, found evidence that each enhancer can act in trans However, the degree to which trans-action was supported varied greatly between enhancers. Quantitative analysis of enhancer activity supports a model wherein an enhancer's strength of transcriptional activation is a major determinant of its ability to act in trans, but that additional factors may also contribute to an enhancer's trans-activity. In sum, our data suggest that a capacity to activate a promoter on a paired chromosome is common among Drosophila enhancers.