Folding Keratin Gene Clusters During Skin Specification
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ABSTRACT:
PROVIDER: PRJNA561632 | ENA |
REPOSITORIES: ENA
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Project description:Regional specification is critical for skin development, regeneration and evolution. The contribution of epigenetics in this process remains unknown. Here using avian epidermis we find two major strategies regulate β-keratin gene clusters. 1) Over the body, macro-regional specificities (scales, feathers, claws, etc) established by typical enhancers control five sub-clusters located within the epidermal differentiation complex on chromosome 25; 2) Within a feather, micro-regional specificities are orchestrated by temporo-spatial chromatin looping of the feather β-keratin gene cluster on chromosome 27. Analyses suggest a 3-factor model for regional specification: competence factors (e.g., AP1) make chromatin accessible, regional specifiers (e.g., Zic1) target specific genome regions, and chromatin organizers (e.g., CTCF, SATB2) establish looping configurations. Gene perturbations disrupt morphogenesis and histo-differentiation. This chicken skin paradigm advances our understanding of how regulation of big gene clusters can set up a two-dimensional body surface map.
2020-06-08 | GSE136224 | GEO
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Project description:Animals develop skin regional specificities to best adapt to their environments. Birds are excellent models in which to study the epigenetic mechanisms that facilitate these adaptions. Patients suffering from SATB2 mutations exhibit multiple defects including ectodermal dysplasia-like changes. The preferential expression of SATB2, a chromatin regulator, in feather-forming compared to scale-forming regions, suggests it functions in regional specification of chicken skin appendages by acting on either differentiation or morphogenesis. Retrovirus mediated SATB2 misexpression in developing feathers, beaks, and claws causes epidermal differentiation abnormalities (e.g. knobs, plaques) with few organ morphology alterations. Chicken β-keratins are encoded in 5 sub-clusters (Claw, Feather, Feather-like, Scale, and Keratinocyte) on Chromosome 25 and a large Feather keratin cluster on Chromosome 27. Type I and II α-keratin clusters are located on Chromosomes 27 and 33, respectively. Transcriptome analyses showed these keratins 1) are often tuned up or down collectively as a sub-cluster, and 2) these changes occur in a temporo-spatial specific manner. This cluster-level suppression is also seen in MMPs on Chromosome 1. SATB2 alters gene expression changes of most other transcripts without this cluster-level switching. These results suggest an organizing role of SATB2 in cluster-level gene co-regulation during skin regional specification.
2021-08-14 | GSE178651 | GEO
Project description:The epidermal barrier protects the body against mechanical injury, infection and dehydration. The respective contribution of type I and type II keratins which form the major cytoskeleton in epidermal keratinocytes in barrier formation and stress protection is incompletely understood. Here, we reveal a novel mechanism by which keratins control anti-oxidant responses through barrier-dependent and cell-autonomous mechanisms. Mice lacking the entire type I (KtyI) or type II (KtyII) keratin gene clusters suffer from distinct prenatal barrier defects. Comparative transcriptome profiling identifies essential cornified envelope components and reveals strong upregulation of the bZIP transcription factor Nrf2 in situ. Isolated keratinocytes from both strains of mice show elevated mitochondrial oxygen consumption and Nrf2 activity, decreased upon keratin re-expression. We propose a model in which keratins control mitochondria-derived oxidative stress via Nrf2 activation. Our findings reveal major contributions of keratins to chronic inflammation and autoimmune disorders. Total RNA obtained from E18.5 embryo back skin from typeI and II keratin knockout compared with respective wild type.
2016-03-26 | E-GEOD-79590 | biostudies-arrayexpress
Project description:The epithelial specific keratin pair, Keratin 8/18 (K8/18), has been reported to be aberrantly expressed in squamous cell carcinoma (SCC) which is also correlated with increased invasiveness and poor prognosis. A Majority of Keratin 8 (K8) functions are governed by its phosphorylation at Serine73 (head domain) and Serine431 (tail domain) residues. Although deregulation of K8 phosphorylation has been associated with progression of different carcinomas, its role in skin SCC and the underlying mechanism is obscured. To understand the molecular basis of K8 phosphorylation mediated regulation of skin SCC progression, we performed TMT-based quantitative phosphoproteomics by expressing K8 wild type, phosphodead and phosphomimetic mutants in K8 deficient A431 cells. Bioinformatic analysis of our phosphoproteomic data showed differential regulation of phosphoproteins associated with migratory, proliferative and invasive potential in these cells. Further validation of protein phosphorylation levels and phenotypic validation of our phosphoproteomic data suggested potential role of K8 site specific phosphorylation/dephosphorylation in neoplastic progression of A431 cells.
2018-07-05 | PXD005301 | Pride
Project description:Epidermolysis bullosa simplex (EBS) is a skin disorder caused by mutations in keratin (K) 5 or K14 genes. It is widely regarded as a mechanobullous disease, resulting from a weakened cytoskeleton, causing extensive cytolysis. It was postulated by others that certain K14 mutations induce TNF-alfa and increase apoptosis. Here, we report that in K5-/- mice , the mRNA and protein levels of TNF-alfa remain unaltered. Transcriptome analysis of K5-/- mice revealed however, that the pro-inflammatory cytokines interleukin-6 and interleukin-1beta were significantly upregulated at the mRNA level in K5-/- mouse skin. These results were confirmed by TaqMan real-time PCR and ELISA assays. We hypothesize that keratin mutations contribute to EBS in a mouse model by inducing local inflammation that mediates a stress response. Experiment Overall Design: Two groups were K5-/- skin and wildtype . Six animals were included in each group. All the total RNA samples were isolated from tissues taken immediately after birth, and were pooled for later microarray experiments. Using realtime PCR and ELISA analysis confirmed our microarray result.
2008-06-15 | E-GEOD-7663 | biostudies-arrayexpress
Project description:Atopic dermatitis (AD) is a pruritic and inflammatory disorder characterized by elevated levels of thymic stromal lymphopoietin (TSLP). Pruritus is prevalent in epidermolysis bullosa (EB). Currently, epidermal barrier disruption is known to trigger TSLP upregulation, however, mechanisms controlling TSLP expression remain incompletely understood. Tslp levels were highly upregulated in the epidermis and in the serum of keratin-deficient mice. Cultured keratinocytes either lacking keratins or expressing the dominant K14p.Arg131Pro show highly increased TSLP. Re-expression of wild-type K14 normalized TSLP levels. We demonstrate that keratins regulate Tslp expression in parts through MEK1/2 activation. The finding that 8 out of 17 EBS patients show elevated TSLP serum levels supports a major role of keratins in TSLP regulation. Our data identify a novel, keratin-dependent and cell-intrinsic regulation of Tslp. Elevated TSLP levels likely explain the high prevalence of pruritus in EBS and additional forms of EB, suggesting TSLP as novel biomarker for pruritus in EB. MEK1/2, in addition to calcineurin inhibitors, might be suitable drugs to treat itch in EB. Investigation was carried out using Keratin deficient keratinocytes isolated from typeI keratin mice.
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Project description:Skin and its appendages such as hair follicle and sweat gland are formed by Keratin-5 expressing (Krt5+) epidermal cells that are specified from primitive, Keratin-8 expressing (Krt8+) ectodermal progenitors shortly after gastrulation. Here we show that transcription factor ∆Np63 is required for converting Krt8+ ectodermal progenitors to Krt5+ epidermal progenitors and priming the underlying dermal cells to form dermal condensate by activating the Wnt/ß-Catenin pathway. These findings unearth the molecular cascades during the fate specification of epidermal cells, illuminate the essential role of ∆Np63 in initiating the Wnt signaling in the epidermis and programming the underlying dermal cells and provide new possibilities to harness the intrinsic developmental program for generating the skin and its appendages.
2018-09-05 | GSE102086 | GEO
Project description:Skin and its appendages such as hair follicle and sweat gland are formed by Keratin-5 expressing (Krt5+) epidermal cells that are specified from primitive, Keratin-8 expressing (Krt8+) ectodermal progenitors shortly after gastrulation. Here we show that transcription factor ∆Np63 is required for converting Krt8+ ectodermal progenitors to Krt5+ epidermal progenitors and priming the underlying dermal cells to form dermal condensate by activating the Wnt/ß-Catenin pathway. These findings unearth the molecular cascades during the fate specification of epidermal cells, illuminate the essential role of ∆Np63 in initiating the Wnt signaling in the epidermis and programming the underlying dermal cells and provide new possibilities to harness the intrinsic developmental program for generating the skin and its appendages.
2018-09-05 | GSE97213 | GEO