Mouse Epidermis Research Articles

Apoptosis and tissue thinning contribute to symmetric cell division in the developing mouse epidermis in a nonautonomous way

Apoptosis and tissue thinning contribute to symmetric cell division in the developing mouse epidermis in a nonautonomous way

Aged and young mice differentially respond to tape-stripping in epidermal gene expression.

Disruption of epidermal permeability barrier induces an increase in proinflammatory cytokine expression and release, stimulation of epidermal lipid and DNA synthesis, and expression of antimicrobial peptides. Although alterations in epidermal function in the aged skin are known, whether the epidermal transcriptomic responses to barrier disruption differ between aged and young mice remains unknown. Here, we performed RNA sequencing of the epidermis in 2-month- vs. 20-month-old mice following barrier disruption with repeated tape-stripping. At baseline condition, the epidermis of 20-month-old mice displayed an upregulation of inflammation-associated genes and down-regulation of epidermal structure- and development-related genes in comparison to 2-month-old mice. Barrier disruption upregulated expression levels of 327genes and downregulated 209genes in 2-month-old mice. In 20-month-old mice, the numbers of upregulated and down-regulated genes were 537 and 299, respectively. In comparison to young mice, the prominently upregulated genes in the 20-month-old mice were associated with the IL-17signalling pathway, while downregulated genes were mainly involved in the cytokine-cytokine receptor interaction pathway. These results indicate that inflammation-associated signalling pathways are upregulated, while epidermal structure- and development-related genes are downregulated in the epidermis of aged mice, with further aggravation following barrier disruption, suggesting the importance of improving epidermal function in the elderly.

106 Dysfunctional mTORC2 signalling as potential risk factor for inflammatory skin diseases

The aim of the presented study was to identify regulators and effectors by which the skin orchestrates balanced defense while promoting regenerative responses to maintain skin barrier integrity and function during life. The mTOR (mammalian target of rapamycin) signalling pathway is essential for cell growth and metabolism. Mutations altering mTOR signalling have been implicated in diabetes, cancer as well as skin diseases. Here we unraveled a specific role of mTORC2 signalling in epidermal barrier formation. Epidermal mTORC2 signalling was disrupted by deleting Rictor, encoding an essential subunit of mTORC2 in mouse epidermis (RicEKO). Epidermal structure and barrier function were investigated by a combination of gene expression, biochemical, morphological and functional analysis in RicEKO and control mice. RicEKO newborns displayed an ichthyosis-like phenotype characterized by dysregulated epidermal de novo lipid synthesis, altered lipid lamellae structure, and aberrant filaggrin processing. Impaired epidermal function in RicEKO mice was demonstrated by increased transepidermal water loss, enhanced corneocyte fragility, perturbed immune cell composition, an exaggerated percutaneous immune response, and an enhanced type 2 immune signature in the skin. Restoration of Akt-Ser473 phosphorylation in mTORC2-deficient keratinocytes by expression of constitutive Akt rescued filaggrin processing. Our findings reveal a critical metabolic signalling relay of barrier formation where epidermal mTORC2 activity controls filaggrin processing and de novo epidermal lipid synthesis during cornification. mTORC2-regulated pathways are druggable and could serve as potential novel therapeutic targets to restore barrier function in inflammatory skin diseases.

198 Il-33 is a central mediator of necroptosis-induced skin inflammation

Necroptosis is a form of programmed necrosis dependent on Receptor Interacting Protein Kinase 3 (RIPK3) and Mixed Lineage Kinase domain Like pseudokinase (MLKL). It is antagonised by apoptotic effectors FADD and caspase-8. Necroptosis has been shown previously to trigger psoriasis-like skin inflammation in mice upon epidermal-specific deletion of FADD or caspase-8 (FADD or caspase-8EKO). Here, we show that alarmin IL-33 is highly expressed in necroptotic epidermis of caspase-8EKO mice and induces the inflammatory cascade upon keratinocyte necroptosis. Genetic ablation of IL-33 or its receptor ST2 (or IL-33R) dramatically delays lesion development and improves survival in caspase-8EKO animals. Interestingly, impairment of the IL33-IL33R axis does not affect epidermal necroptosis but reduces immune cell recruitment and subsequent amplification of inflammation. Recent data in the literature have highlighted expression IL-33 in the epidermis of psoriasis patients. Taken together, our findings highlight a pivotal role of IL-33 in necroptosis- induced psoriasis-like skin inflammation.

Simulations reveal that different responses to cell crowding determine the expansion of p53 and Notch mutant clones in squamous epithelia.

During ageing, normal epithelial tissues progressively accumulate clones carrying mutations that increase mutant cell fitness above that of wild-type cells. Such mutants spread widely through the tissues, yet despite this cellular homeostasis and functional integrity of the epithelia are maintained. Two of the genes most commonly mutated in human skin and oesophagus are p53 and Notch1, both of which are also recurrently mutated in cancers of these tissues. From observations taken in human and mouse epithelia, we find that clones carrying p53 and Notch pathway mutations have different clone dynamics which can be explained by their different responses to local cell crowding. p53 mutant clone growth in mouse epidermis approximates a logistic curve, but feedbacks responding to local crowding are required to maintain tissue homeostasis. We go on to show that the observed ability of Notch pathway mutant cells to displace the wild-type population in the mouse oesophageal epithelium reflects a local density feedback that affects both mutant and wild-type cells equally. We then show how these distinct feedbacks are consistent with the distribution of mutations observed in human datasets and are suggestive of a putative mechanism to constrain these cancer-associated mutants.

UV-induced reduction in Polycomb repression promotes epidermal pigmentation.

Ultraviolet (UV) radiation is a prime environmental stressor that our epidermis is exposed to on a daily basis. To avert UV-induced damage, epidermal stem cells (EpSCs) become pigmented via a process of heterotypic interaction between melanocytes and EpSCs; however, the molecular mechanisms of this interaction are not well understood. In this study, we show that the function of a key chromatin regulator, the Polycomb complex, was reduced upon UV exposure in human and mouse epidermis. Genetic ablation of key Polycomb subunits in murine EpSCs, mimicking depletion upon UV exposure, results in an increased number of epidermal melanocytes and subsequent epidermal pigmentation. Genome-wide transcriptional and chromatin studies show that Polycomb regulates the expression of UV-responsive genes and identifies type II collagen (COL2A1) as a critical secreted regulator of melanogenesis and epidermal pigmentation. Together, our findings show how UV exposure induces Polycomb-mediated changes in EpSCs to affect melanocyte behavior and promote epidermal pigmentation.

Troy/Tnfrsf19 marks epidermal cells that govern interfollicular epidermal renewal and cornification.

SummaryThe skin epidermis is a highly compartmentalized tissue consisting of a cornifying epithelium called the interfollicular epidermis (IFE) and associated hair follicles (HFs). Several stem cell populations have been described that mark specific compartments in the skin but none of them is specific to the IFE. Here, we identify Troy as a marker of IFE and HF infundibulum basal layer cells in developing and adult human and mouse epidermis. Genetic lineage-tracing experiments demonstrate that Troy-expressing basal cells contribute to long-term renewal of all layers of the cornifying epithelium. Single-cell transcriptomics and organoid assays of Troy-expressing cells, as well as their progeny, confirmed stem cell identity as well as the ability to generate differentiating daughter cells. In conclusion, we define Troy as a marker of epidermal basal cells that govern interfollicular epidermal renewal and cornification.

The anti-apoptotic Bcl-2 protein regulates hair follicle stem cell function

Maintaining the architecture, size and composition of an intact stem cell (SC) compartment is crucial for tissue homeostasis and regeneration throughout life. In mammalian skin, elevated expression of the anti-apoptotic Bcl-2 protein has been reported in hair follicle (HF) bulge SCs (BSCs), but its impact on SC function is unknown. Here, we show that systemic exposure of mice to the Bcl-2 antagonist ABT-199/venetoclax leads to the selective loss of suprabasal BSCs (sbBSCs), thereby disrupting cyclic HF regeneration. RNAseq analysis shows that the pro-apoptotic BH3-only proteins BIM and Bmf are upregulated in sbBSCs, explaining their addiction to Bcl-2 and the marked susceptibility to Bcl-2 antagonism. In line with these observations, conditional knockout of Bcl-2 in mouse epidermis elevates apoptosis in BSCs. In contrast, ectopic Bcl-2 expression blocks apoptosis during HF regression, resulting in the accumulation of quiescent SCs and delaying HF growth in mice. Strikingly, Bcl-2-induced changes in size and composition of the HF bulge accelerate tumour formation. Our study identifies a niche-instructive mechanism of Bcl-2-regulated apoptosis response that is required for SC homeostasis and tissue regeneration, and may suppress carcinogenesis.

Secreted PEDF modulates fibroblast collagen synthesis through M1 macrophage polarization under expanded condition

Tissue expansion is widely used to obtain new skin tissue for repairing defects in the clinical practice of plastic surgery. One major complication can be dermal thinning during expansion, which usually leads to skin rupture. Collagen synthesis can determine dermal thickness and can be influenced by macrophage polarization during expansion. The aim of the study was to test whether pigment epithelium-derived factor (PEDF) could be a modulator of collagen synthesis in fibroblasts by regulating macrophage polarization during skin expansion. Our results showed that PEDF mRNA expression was increased in expanded human and mouse epidermis. PEDF protein levels were elevated in the subcutaneous exudates of a rat skin expansion model. Increased PEDF mRNA expression was accompanied by dermal thinning during a three-week expansion protocol. Subcutaneous injection of PEDF in vivo further resulted in dermal thinning and cell number increase of M1 macrophage in the expanded skin. PEDF also promoted macrophage polarization in vitro to the M1 subtype under hypoxic conditions. PEDF did not influence collagen gene expression in fibroblasts directly, but attenuated collagen synthesis in a macrophage-mediated manner. Additionally, blockage of PEDF receptors on macrophages with inhibitors rescued collagen synthesis in fibroblasts. Our research demonstrated PEDF elevation in expanded skin leads to dermal thinning through M1 macrophage-mediated collagen synthesis inhibition in fibroblasts. Our results could form a basis for the development of novel strategies to improve skin integrity in expanded skin by using PEDF.

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation.

Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (27a), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E2 synthase-1. Compound 27a is metabolized by sulfation and β-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead.

HDAC1/2 Control Proliferation and Survival in Adult Epidermis and Pre‒Basal Cell Carcinoma through p16 and p53

HDAC inhibitors show therapeutic promise for skin malignancies; however, the roles of specific HDACs in adult epidermal homeostasis and in disease are poorly understood. We find that homozygous epidermal codeletion of Hdac1 and Hdac2 in adult mouse epidermis causes reduced basal cell proliferation, apoptosis, inappropriate differentiation, and eventual loss of Hdac1/2-null keratinocytes. Hdac1/2-deficient epidermis displays elevated acetylated p53 and increased expression of the senescence gene p16. Loss of p53 partially restores basal proliferation, whereas p16 deletion promotes long-term survival of Hdac1/2-null keratinocytes. In activated GLI2-driven pre-basal cell carcinoma, Hdac1/2 deletion dramatically reduces proliferation and increases apoptosis, and knockout of either p53 or p16 partially rescues both proliferation and basal cell viability. Topical application of the HDAC inhibitor romidepsin to the normal epidermis or to GLI2ΔN-driven lesions produces similar defects to those caused by genetic Hdac1/2 deletion, and these are partially rescued by loss of p16. These data reveal essential roles for HDAC1/2 in maintaining proliferation and survival of adult epidermal and basal cell carcinoma progenitors and suggest that the efficacy of therapeutic HDAC1/2 inhibition will depend in part on the mutational status of p53 and p16.

Peroxisomal Fatty Acid Oxidation and Glycolysis Are Triggered in Mouse Models of Lesional Atopic Dermatitis

Alterations of the lipid profile of the stratum corneum have an important role in the pathogenesis of atopic dermatitis (AD) because they contribute to epidermal barrier impairment. However, they have not previously been envisioned as a cellular response to altered metabolic requirements in AD epidermis. In this study, we report that the lipid composition in the epidermis of flaky tail, that is, ft/ft mice mimics that of human lesional AD (ADL) epidermis, both showing a shift toward shorter lipid species. The amounts of C24 and C26 free fatty acids and C24 and C26 ceramides—oxidized exclusively in peroxisomes—were reduced in the epidermis of ft/ft mice despite increased lipid synthesis, similar to that seen in human ADL edpidermis. Increased ACOX1 protein and activity in granular keratinocytes of ft/ft epidermis, altered lipid profile in human epidermal equivalents overexpressing ACOX1, and increased ACOX1 immunostaining in skin biopsies from patients with ADL suggest that peroxisomal β-oxidation significantly contributes to lipid signature in ADL epidermis. Moreover, we show that increased anaerobic glycolysis in ft/ft mouse epidermis is essential for keratinocyte proliferation and adenosine triphosphate synthesis but does not contribute to local inflammation. Thus, this work evidenced a metabolic shift toward enhanced peroxisomal β-oxidation and anaerobic glycolysis in ADL epidermis.

MC5R Contributes to Sensitivity to UVB Waves and Barrier Function in Mouse Epidermis

MC5R is known for its role in the exocrine function of sebaceous glands, but other functions in the epidermis remain unclear. This study focused on the relationship between MC5R and homeostasis in the epidermis and examined the role of MC5R in mice whose skin was irradiated with UVB waves. UVB irradiation-induced skin ulcers and severe inflammation at lower doses in homozygotes of MC5R-deficient (i.e., MC5R−/−) mice (150 mJ/cm2) than the doses in wild-type mice (500 mJ/cm2). Transepidermal water loss was increased (approximately 10-fold) in adult MC5R−/− mice compared with that in wild-type mice. In neonates, a dye exclusion assay showed no remarkable difference between MC5R−/− and wild-type mice. After UVB irradiation, compared with wild-type mice, MC5R−/− mice showed increased inflammatory cell infiltration in the dermis of the ulcerative region, significantly increased thickness of the epidermis in the nonulcerative region, significantly more prickle cells in the nonulcerative region, and increased serum IL-6 levels but decreased IL-10 levels. Transmission electron microscopy revealed fewer lamellar granules, less lipid secretion, and an expansion of the trans-Golgi network in the epidermis in MC5R−/− mice. This study elucidated the increased sensitivity to UVB irradiation and decreased barrier function in MC5R−/−mice.

Pathogenic and Compensatory Mechanisms in Epidermis of Sphingomyelin Synthase 2-Deficient Mice

Sphingomyelin (SM) is a constituent of cellular membranes, while ceramides (Cer) produced from SM on plasma membranes serve as a lipid mediator that regulates cell proliferation, differentiation, and apoptosis. In the skin, SM also is a precursor of Cer, an important constituent of epidermal permeability barrier. We investigated the role of epidermal SM synthase (SMS)2, an isoform of SMS, which modulates SM and Cer levels on plasma membranes. Although SMS2-knockout (SMS2-KO) mice were not neonatal lethal, an ichthyotic phenotype with epidermal hyperplasia and hyperkeratosis was evident at birth, which persisted until 2 weeks of age. These mice showed abnormal lamellar body morphology and secretion, and abnormal extracellular lamellar membranes in the stratum corneum. These abnormalities were no longer evident by 4 weeks of age in SMS2-KO mice. Our study suggests that (1) exposure to a dry terrestrial environment initiates compensatory responses, thereby normalizing epidermal ichthyotic abnormalities and (2) that a nonlethal gene abnormality can cause an ichthyotic skin phenotype.

Key changes in chromatin mark mammalian epidermal differentiation and ageing

ABSTRACT Dynamic shifts in chromatin states occur during embryonic epidermal development to support diverse epigenetic pathways that regulate skin formation and differentiation. However, it is not known whether the epigenomes established during embryonic development are maintained into adulthood or how these epigenetic mechanisms may be altered upon physiological ageing of the tissue. Here, we systematically profiled the nuclear enrichment of five key histone modifications in young and aged mouse epidermis and identified distinct chromatin states that are tightly correlated with cellular differentiation, as well as chromatin alterations that accompanied epidermal ageing. Our data showed that histone modifications, which become differentially enriched in undifferentiated basal or differentiated suprabasal cells during embryonic development, retained their distinct cell-type specific enrichment patterns in both young and aged adult tissues. Specifically, high levels of H3K4me3, H4K20me1 and H4K16ac marked the proliferative basal cells, while differentiated suprabasal cells accumulated H3K27me3 and H4K20me3 heterochromatin with a concomitant deacetylation of H4K16. We further identified shifts in the chromatin in the aged basal epidermis, which exhibited markedly reduced levels of H4K16ac, absence of high H4K20me1 staining and increased cell-to-cell variability in total histone H3 and H4 content. Changes in the chromatin profiles in aged tissues paralleled the altered expression of their corresponding histone modifiers in the basal keratinocytes. These results thus reveal the key histone signatures of epidermal differentiation that are conserved from embryonic development to adult homoeostasis, and provide insights into the epigenetic pathways underlying physiological skin ageing.

Decreased Calcium-Sensing Receptor Expression Controls Calcium Signaling and Cell-To-Cell Adhesion Defects in Aged Skin

The calcium-sensing receptor (CaSR) drives essential calcium ion (Ca2+) and E-cadherin‒mediated processes in the epidermis, including differentiation, cell-to-cell adhesion, and epidermal barrier homeostasis in cells and inyoung adult mice. We now report that decreased CaSR expression leads to impaired Ca2+ signal propagation in aged mouse (aged >22 months) epidermis and human (aged >79 years, donor age) keratinocytes. Baseline cytosolic Ca2+ concentrations were higher, and capacitive Ca2+ entry was lower in aged than in young keratinocytes. As in Casr-knockout mice (EpidCaSR-/-), decreased CaSR expression led to decreased E-cadherin and phospholipase C-γ expression and to a compensatory upregulation of STIM1. Pretreatment with the CaSR agonist N-(3-[2-chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine normalized Ca2+ propagation and E-cadherin organization after experimental wounding. These results suggest that age-related defects in CaSR expression dysregulate normal keratinocyte and epidermal Ca2+ signaling, leading to impaired E-cadherin expression, organization, and function. These findings show an innovative mechanism whereby Ca2+- and E-cadherin‒dependent functions are impaired in aging epidermis and suggest a new therapeutic approach by restoring CaSR function.

126 EphA2 is a novel regulator of autolysosome recycling at end-stage autophagy and a key regulator in epidermal proliferation

Abnormal autophagy is observed in several skin diseases associated with hyperproliferation. We have shown that Beclin1 is increased in psoriatic lesions and when Beclin1 is conditionally knocked out in the epidermis, imiquimod(IMQ)-induced hyperproliferation is markedly attenuated. This indicates that autophagy plays a positive role in psoriasis and contributes to epidermal hyperproliferation in psoriatic lesions. However, how autophagy is regulated in the epidermis of psoriatic lesions is a knowledge gap that needs to be filled. We show that loss of EphA2, a receptor tyrosine kinase, reduces proliferation in mouse epidermis and human keratinocytes. Importantly, expression of EphA2 was shown to be increased in psoriatic lesions. We demonstrate that knockdown of EphA2 in HEKs results in an increase in: (i) large vacuoles; and (ii) LC3II protein, a marker for autophagosomes. To further explore this defect in autophagy, we measured autophagy flux by two well-established approaches: LC3II turnover and p62 levels, and found that loss of EphA2 reduced LC3II turnover in HEKs; and increased p62 in HEKs as well as in mouse epidermis, indicating an inhibition of autophagy flux. To determine the novel interactors of EphA2 in autophagy, we conducted BioID and co-immunoprecipitation assays and confirmed that among the novel binding partners of EphA2 was phospholipase D1 (PLD1). We have shown that PLD1 is a critical regulator of autolysosome recycling at end-stage autophagy. We have also demonstrated that the activity of dynamin1 (one of key players in autolysosome recycling at end-stage autophagy) and its association with autolysosomes is inhibited by PDL1/PKC pathway in HEKs. EphA2 affects autolysosome recycling via inhibiting PLD1/PKC signaling and thus ensuring dynamin1 activity and its association with autolysosome. Thus, we conclude that upregulation of EphA2 in the “activated” epidermis contributes to enhanced autophagy and consequently a hyperproliferative state.

The transmembrane protein LRIG1 triggers melanocytic tumor development following chemically induced skin carcinogenesis

The incidence of melanoma and nonmelanoma skin cancer has increased tremendously in recent years. Although novel treatment options have significantly improved patient outcomes, the prognosis for most patients with an advanced disease remains dismal. It is, thus, imperative to understand the molecular mechanisms involved in skin carcinogenesis in order to develop new targeted treatment strategies. Receptor tyrosine kinases (RTK) like the ERBB receptor family, including EGFR/ERBB1, ERBB2/NEU, ERBB3, and ERBB4, are important regulators of skin homeostasis and their dysregulation often results in cancer, which makes them attractive therapeutic targets. Members of the leucine‐rich repeats and immunoglobulin‐like domains protein family (LRIG1‐3) are ERBB regulators and thus potential therapeutic targets to manipulate ERBB receptors. Here, we analyzed the function of LRIG1 during chemically induced skin carcinogenesis in transgenic mice expressing LRIG1 in the skin under the control of the keratin 5 promoter (LRIG1‐TG mice). We observed a significant induction of melanocytic tumor formation in LRIG1‐TG mice and no difference in papilloma incidence between LRIG1‐TG and control mice. Our findings also revealed that LRIG1 affects ERBB signaling via decreased phosphorylation of EGFR and increased activation of the oncoprotein ERBB2 during skin carcinogenesis. The epidermal proliferation rate was significantly decreased during epidermal tumorigenesis under LRIG1 overexpression, and the apoptosis marker cleaved caspase 3 was significantly activated in the epidermis of transgenic LRIG1 mice. Additionally, we detected LRIG1 expression in human cutaneous squamous cell carcinoma and melanoma samples. Therefore, we depleted LRIG1 in human melanoma cells (A375) by CRISPR/Cas9 technology and found that this caused EGFR and ERBB3 downregulation in A375 LRIG1 knockout cells 6 h following stimulation with EGF. In conclusion, our study demonstrated that LRIG1‐TG mice develop melanocytic skin tumors during chemical skin carcinogenesis and a deletion of LRIG1 in human melanoma cells reduces EGFR and ERBB3 expression after EGF stimulation.

Twist1 is required for the development of UVB-induced squamous cell carcinoma.

The transcription factor Twist1 has been reported to be essential for the formation and invasiveness of chemically induced tumors in mouse skin. However, the impact of keratinocyte-specific Twist1 deletion on skin carcinogenesis caused by UVB radiation has not been reported. Deletion of Twist1 in basal keratinocytes of mouse epidermis using K5.Cre × Twist1flox/flox mice led to significantly reduced UVB-induced epidermal hyperproliferation. In addition, keratinocyte-specific deletion of Twist1 significantly suppressed UVB-induced skin carcinogenesis. Further analyses revealed that deletion of Twist1 in cultured keratinocytes or mouse epidermis in vivo led to keratinocyte differentiation. In this regard, deletion of Twist1 in epidermal keratinocytes showed significant induction of early and late differentiation markers, including TG1, K1, OVOL1, loricrin, and filaggrin. Similar results were obtained with topical application of harmine, a Harmala alkaloid that leads to degradation of Twist1. In contrast, overexpression of Twist1 in cultured keratinocytes suppressed calcium-induced differentiation. Further analyses using both K5.Cre × Twist1flox/flox mice and an inducible system where Twist1 was deleted in bulge region keratinocytes showed loss of expression of hair follicle stem/progenitor markers, including CD34, Lrig1, Lgr5, and Lgr6. These data support the conclusion that Twist1 has a direct role in maintaining the balance between proliferation and differentiation of keratinocytes and keratinocyte stem/progenitor populations. Collectively, these results demonstrate a critical role for Twist1 early in the process of UVB skin carcinogenesis, and that Twist1 may be a novel target for the prevention of cutaneous squamous cell carcinoma.

Getting under the skin of Polycomb-dependent gene regulation

The Polycomb repressive system functions through chromatin to regulate gene expression and development. In this issue of Genes & Development, Cohen and colleagues (pp. 354-366) use the developing mouse epidermis as a model system to show that the two central Polycomb repressive complexes, PRC1 and PRC2, have autonomous yet overlapping functions in repressing Polycomb target genes. They show that this cooperation enables the stable repression of nonepidermal transcription factors that would otherwise compromise epidermal cell identity and disrupt normal skin development.