Chromatin looping links target genes with genetic risk loci for dermatological traits
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE151193 | GEO | 2020/05/27
REPOSITORIES: GEO
Similar Datasets
Project description:Whether epidermal factors play a primary role in immune-mediated skin diseases such as psoriasis is unknown. We now show that the pro-differentiation transcription factor Grainyhead-like 3 (GRHL3), essential during epidermal development but dispensable in adult skin homeostasis, is required for barrier repair after adult epidermal injury. Consistent with activation of a GRHL3-regulated repair pathway in psoriasis, we find GRHL3 up-regulation in lesional skin where GRHL3 binds known epidermal differentiation gene targets. Furthermore, we show the functionality of this pathway in the Imiquimod mouse model of immune-mediated epidermal hyperplasia where loss of Grhl3 exacerbates the epidermal damage response, conferring greater sensitivity to disease induction, delayed resolution of epidermal lesions, and resistance to anti-IL-22 therapy. ChIP-seq and gene expression profiling studies show that while GRHL3 regulates differentiation genes both in development and during repair from immune-mediated damage, it targets distinct sets of genes in the two processes. In particular, GRHL3 suppresses a number of alarmin and other pro-inflammatory genes after immune injury. This study identifies a GRHL3-regulated epidermal barrier repair pathway that suppresses disease initiation and helps resolve existing lesions in immune-mediated epidermal hyperplasia. A single timepoint was assessed after physical injury of the epidermal barrier and two timepoints were assessed after immune mediated injury of the epidermis following Imiquimod treatment (psoriasis mouse model)
2014-10-01 | E-GEOD-59384 | biostudies-arrayexpress
Project description:Whether epidermal factors play a primary role in immune-mediated skin diseases such as psoriasis is unknown. We now show that the pro-differentiation transcription factor Grainyhead-like 3 (GRHL3), essential during epidermal development but dispensable in adult skin homeostasis, is required for barrier repair after adult epidermal injury. Consistent with activation of a GRHL3-regulated repair pathway in psoriasis, we find GRHL3 up-regulation in lesional skin where GRHL3 binds known epidermal differentiation gene targets. Furthermore, we show the functionality of this pathway in the Imiquimod mouse model of immune-mediated epidermal hyperplasia where loss of Grhl3 exacerbates the epidermal damage response, conferring greater sensitivity to disease induction, delayed resolution of epidermal lesions, and resistance to anti-IL-22 therapy. ChIP-seq and gene expression profiling studies show that while GRHL3 regulates differentiation genes both in development and during repair from immune-mediated damage, it targets distinct sets of genes in the two processes. In particular, GRHL3 suppresses a number of alarmin and other pro-inflammatory genes after immune injury. This study identifies a GRHL3-regulated epidermal barrier repair pathway that suppresses disease initiation and helps resolve existing lesions in immune-mediated epidermal hyperplasia.
2014-10-01 | GSE59384 | GEO
Project description:Epidermal barrier repair mechanisms activated in psoriasis lesions are likely involved in limiting the severity of this disease. We show that loss of grainyhead-like 3 (Grhl3), a pro-terminal differentiation factor in the epidermis, is sufficient to trigger greater sensitivity to and delayed resolution of epidermal lesions resulting from either physical or immune mediated barrier injury. After stimulation of Toll like receptors, the loss of Grhl3 resulted in increased epidermal damage with a striking increase in basal cell proliferation, hyperplasia of partially differentiated suprabasal layers, and a transcriptional profile highlighted by the overexpression of epidermal wound response and alarmin genes. This study reveals an important role for the epidermis in the initiation and recovery from immune-mediated lesions, and indicated that the epidermal regulator Grhl3 acts to both suppress disease initiation and resolve existing lesions. This work suggests that treatments focused on improving barrier function could be used preventatively and therapeutically in psoriasis. Whole skin was collected from E16.5 mouse backskins for Grhl3 ChIP. Adult epidermis for depilation and imiquimod experiments was seperated from dermis using dispase prior to Grhl3 ChIP.
2014-09-01 | E-GEOD-52648 | biostudies-arrayexpress
Project description:The skin is vital for protecting the body and perceiving external stimuli in the environment. Ability to adapt between environments is in part based on skin plasticity, indicating evolved homeostasis between skin and environment. This homeostasis reflects the greater relationship between the body and the environment, and disruptions in this balance may lead to accumulation of susceptibility factors for autoimmune disorders like psoriasis. We collected skin tissue biopsies from individuals with psoriasis and compared gene expression in psoriatic plaques to non-plaque psoriatic skin. We then compared these data with non-psoriatic skin transcriptome data from multiple primate species. We found 67 genes showing human-specific skin expression that are also differentially regulated in psoriatic skin; these genes are significantly enriched for skin barrier function, immunity, and neuronal development. We identified 6 gene clusters with differential expression in the context of human evolution and psoriasis, suggesting underlying regulatory mechanisms in these loci. Human and psoriasis-specific enrichment of neuroimmune genes shows the importance of the ongoing evolved homeostatic relationship between skin and external environment. These results have implications for both evolutionary medicine and public health, using transcriptomic data to acknowledge the importance of an individual's surroundings on their overall health.
2021-09-16 | GSE183820 | GEO
Project description:Psoriasis is a chronic inflammatory immune-mediated disorder affecting the skin and other organs including joints. Over 1,300 transcripts are altered in psoriatic involved skin compared to normal skin. Global epigenetic profiles of psoriatic skin have not been described. Here we describe the first genome-wide study of altered CpG methylation in psoriatic skin. We determined the methylation levels at 27,578 CpG sites in skin samples from individuals with psoriasis (12 involved, 8 uninvolved) and 10 unaffected individuals. CpG methylation of involved skin differed from normal skin at 1,108 sites. Twelve mapped to the epidermal differentiation complex, upstream or within genes that are highly up-regulated in psoriasis. Hierarchical clustering of 50 of the top differentially methylated (DM) sites separated psoriatic from normal skin samples. CpG sites where methylation was correlated with gene expression are reported. Sites with inverse correlations between methylation and nearby gene expression include those of KYNU, OAS2, S100A12, and SERPINB3, whose strong transcriptional up-regulation are important discriminators of psoriasis. We observed intrinsic epigenetic differences in uninvolved skin. Pyrosequencing of bisulfite-treated DNA from skin biopsies at three DM loci confirmed earlier findings and revealed a reversion of methylation levels towards the non-psoriatic state after one month of anti-TNF-a therapy. Control n=8 (NN), psoriasis involved n = 19 (PP), psoriasis uninvolved n=8 (PN). Hybridized to Illumina Human 27k methylation array. Paired samples are as follows: PN1 and PP1 PN2 and PP2 PN3 and PP3 PN4 and PP4 PN5 and PP5 PN6 and PP6 PN7 and PP7 PN8 and PP8
2011-11-11 | E-GEOD-31835 | biostudies-arrayexpress
Project description:Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. We recently identified the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC, and demonstrated that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Reduced levels of GRHL3 and its target gene PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data defines the miR-21-GRHL3-PTEN-axis as a critical tumor suppressor pathway in SCC. Total RNA was isolated from two SCC primary tissue samples and their matched normal skin controls.
2013-01-18 | E-GEOD-32868 | biostudies-arrayexpress
Project description:Psoriasis is a chronic inflammatory disease of the skin for which current treatments are only partially effective. There is therefore an urgent need to develop novel therapies with higher efficacy through a better understanding of disease aetiology. Recently, it has been demonstrated that individuals with specific mutations in the gene encoding the adapter protein CARD14 have a high risk of developing psoriasis. Psoriasis associated CARD14 mutations result in enhanced activation of NF-kB transcription factors in keratinocytes. The CARD14/NF-kB axis may therefore be central in driving the pathogenesis of psoriasis. The aim of this project is to investigate the molecular mechanisms by which CARD14 activates the NF-kB pathway. Specifically, within this project, we aim to detail the interaction partners of both WT and a gain-of-function mutant CARD14 (E138A) via SILAC and mass spectrometry.
2024-08-27 | PXD033039 | Pride
Project description:Psoriasis is a chronic inflammatory disease of the skin for which current treatments are only partially effective. There is therefore an urgent need to develop novel therapies with higher efficacy through a better understanding of disease aetiology. Recently, it has been demonstrated that individuals with specific mutations in the gene encoding the adapter protein CARD14 have a high risk of developing psoriasis. Psoriasis associated CARD14 mutations result in enhanced activation of NF-kB transcription factors in keratinocytes. The CARD14/NF-kB axis may therefore be central in driving the pathogenesis of psoriasis. The aim of this project is to investigate the molecular mechanisms by which CARD14 activates the NF-kB pathway. Specifically, within this project, we aim to detail the downstream signalling pathways of a gain-of-function mutant CARD14 (E138A) via SILAC and mass spectrometry.
2024-08-27 | PXD033009 | Pride
Project description:Type III interferons (IFN-λ) are antiviral and immunomodulatory cytokines that have been best characterized in respiratory and gastrointestinal infections, but the effects of IFN-λ against skin infections have not been extensively investigated. We sought to define the skin-specific effects of IFN-λ against the highly prevalent human pathogen herpes simplex virus (HSV). We infected mice lacking the IFN-λ receptor (Ifnlr1-/-), both the IFN-λ and the IFN-αβ receptor (Ifnar1-/- Ifnlr1-/-), or IFN-λ cytokines (Ifnl2/3-/-) and found that IFN-λ restricts the severity of HSV-1 and HSV-2 skin lesions, independent of a direct effect on viral load. Using conditional knockout mice, we found that IFN-λ signaling in both keratinocytes and neutrophils was necessary to control HSV-1 skin lesion severity, and that IFN-λ signaling in keratinocytes suppressed CXCL9-mediated neutrophil recruitment to the skin. Furthermore, depleting neutrophils prevented the development of severe HSV-1 skin lesions in Ifnlr1-/- mice. Altogether, our results suggest that IFN-λ plays an immunomodulatory role in the skin that restricts neutrophil-mediated pathology during HSV infection, and suggest potential applications for IFN-λ in treating viral skin infections.
2023-09-12 | GSE242170 | GEO
Project description:Type III interferons (IFN-λ) are antiviral and immunomodulatory cytokines that have been best characterized in respiratory and gastrointestinal infections, but the effects of IFN-λ against skin infections have not been extensively investigated. We sought to define the skin-specific effects of IFN-λ against the highly prevalent human pathogen herpes simplex virus (HSV). We infected mice lacking the IFN-λ receptor (Ifnlr1-/-), both the IFN-λ and the IFN-αβ receptor (Ifnar1-/- Ifnlr1-/-), or IFN-λ cytokines (Ifnl2/3-/-) and found that IFN-λ restricts the severity of HSV-1 and HSV-2 skin lesions, independent of a direct effect on viral load. Using conditional knockout mice, we found that IFN-λ signaling in both keratinocytes and neutrophils was necessary to control HSV-1 skin lesion severity, and that IFN-λ signaling in keratinocytes suppressed CXCL9-mediated neutrophil recruitment to the skin. Furthermore, depleting neutrophils prevented the development of severe HSV-1 skin lesions in Ifnlr1-/- mice. Altogether, our results suggest that IFN-λ plays an immunomodulatory role in the skin that restricts neutrophil-mediated pathology during HSV infection, and suggest potential applications for IFN-λ in treating viral skin infections.
2023-09-12 | GSE242068 | GEO