Regulation of MYC by CARD14 in Human Epithelium is a Determinant of Epidermal Homeostasis and Disease I
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1097507 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28593100.fastq.gz | Fastqsanger.gz | |||
| SRR28593101.fastq.gz | Fastqsanger.gz | |||
| SRR28593102.fastq.gz | Fastqsanger.gz | |||
| SRR28593103.fastq.gz | Fastqsanger.gz | |||
| SRR28593104.fastq.gz | Fastqsanger.gz |
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Project description:Caspase recruitment domain family member 14 (CARD14) and its variants are associated with both atopic dermatitis (AD) and psoriasis, but their mechanistic impact on skin barrier homeostasis is largely unknown. CARD14 is known to signal via NFκB, however, CARD14-NFκB signaling does not fully explain the heterogeneity of CARD14-driven disease. Herein, we describe a direct interaction between CARD14 and MYC and show that CARD14 signals through MYC in keratinocytes to coordinate skin barrier homeostasis. CARD14 directly binds MYC and influences barrier formation in a MYC-dependent fashion, and this mechanism is undermined by disease-associated CARD14 variants. These studies establish a paradigm that CARD14 activation regulates skin barrier function by two distinct mechanisms including activating NFκB to bolster the antimicrobial (chemical) barrier and stimulating MYC to bolster the physical barrier. Finally, we show that CARD14-dependent MYC signaling occurs in other epithelia expanding the impact of our findings beyond the skin.
2024-07-13 | GSE263428 | GEO
Project description:Caspase recruitment domain family member 14 (CARD14) and its variants are associated with both atopic dermatitis (AD) and psoriasis, but their mechanistic impact on skin barrier homeostasis is largely unknown. CARD14 is known to signal via NFκB, however, CARD14-NFκB signaling does not fully explain the heterogeneity of CARD14-driven disease. Herein, we describe a direct interaction between CARD14 and MYC and show that CARD14 signals through MYC in keratinocytes to coordinate skin barrier homeostasis. CARD14 directly binds MYC and influences barrier formation in a MYC-dependent fashion, and this mechanism is undermined by disease-associated CARD14 variants. These studies establish a paradigm that CARD14 activation regulates skin barrier function by two distinct mechanisms including activating NFκB to bolster the antimicrobial (chemical) barrier and stimulating MYC to bolster the physical barrier. Finally, we show that CARD14-dependent MYC signaling occurs in other epithelia expanding the impact of our findings beyond the skin.
2024-07-13 | GSE263420 | GEO
Project description:Regulation of MYC by CARD14 in Human Epithelium is a Determinant of Epidermal Homeostasis and Disease II
| PRJNA1097530 | ENA
Project description:Caspase recruitment domain family member 14 (CARD14) and its variants are associated with both atopic dermatitis (AD) and psoriasis, but their mechanistic impact on skin barrier homeostasis is largely unknown. CARD14 is known to signal via NF-κB; however, CARD14-NF-κB signaling does not fully explain the heterogeneity of CARD14-driven disease. Here, we describe a direct interaction between CARD14 and MYC and show that CARD14 signals through MYC in keratinocytes to coordinate skin barrier homeostasis. CARD14 directly binds MYC and influences barrier formation in an MYC-dependent fashion, and this mechanism is undermined by disease-associated CARD14 variants. These studies establish a paradigm that CARD14 activation regulates skin barrier function by two distinct mechanisms, including activating NF-κB to bolster the antimicrobial (chemical) barrier and stimulating MYC to bolster the physical barrier. Finally, we show that CARD14-dependent MYC signaling occurs in other epithelia, expanding the impact of our findings beyond the skin.
| S-EPMC11469028 | biostudies-literature
Project description:Psoriasis is a common, immune-mediated, genetic disorder of the skin associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosome 17q25.3-qter following a genome-wide linkage scan in a family of European origin with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a multiply affected psoriasis family from Taiwan. With genomic capture and DNA sequencing, we identified unique gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) that segregated with psoriasis. The mutations, c.349G>A (p.Gly117Ser) and c.349+5G>A respectively, altered splicing between exons 3 and 4 of CARD14. A de novo mutation in CARD14, c.413A>C [p.Glu138Ala], was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes compared to wildtype CARD14. These included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, while in lesional psoriatic skin it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the lesional epidermis. We propose that, following a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration that is the hallmark of psoriasis. No replicates are included. Three sample sets. [1] Skin biopsies had RNA extracted for expression within target tissue. [2] HEK cells were transfected with different constructs (including wildtype) of CARD14 to determine the mutational effect in keratinocytes. [3] Keratinocytes derived from psoriasis patients with CARD14 mutations were cultured and compared with and without stimulation with TNFalpha.
2012-05-08 | E-GEOD-36387 | biostudies-arrayexpress
Project description:Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding an NF-kB activator within skin epidermis, account for PSORS2. Here we describe fifteen additional rare, missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There was an excess of rare variants within CARD14 in cases versus controls (burden test p-value = 0.0015). Some variants were only seen in a single case and included putative pathogenic mutations (c.424G>A [p.Glu142Lys], c.425A>G [p.Glu142Gly]) and the generalized pustular psoriasis mutation, c.413A>C (p.Glu138Ala), that lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities, with putative pathogenic variants leading to levels >2.5-fold higher than wildtype CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with TNF-a to achieve significant increases in NF-kB levels. Transcriptome profiling of wildtype and variant CARD14 transfectants in keratinocytes differentiated likely pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped and meta-analysis revealed association of psoriasis with rs11652075 (c.2458C>T/p.Arg820Trp; p-value = 2.1x10-6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease. Keratinocytes were transfected with wildtype Cardsh or one of 16 Card14 mutations (17 total samples). The cells were collected and RNA extracted to determine the effect of these mutations compared to wildtype Card14. No replicates are included.
2012-05-08 | E-GEOD-36381 | biostudies-arrayexpress
Project description:Psoriasis is a common, immune-mediated, genetic disorder of the skin associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosome 17q25.3-qter following a genome-wide linkage scan in a family of European origin with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a multiply affected psoriasis family from Taiwan. With genomic capture and DNA sequencing, we identified unique gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) that segregated with psoriasis. The mutations, c.349G>A (p.Gly117Ser) and c.349+5G>A respectively, altered splicing between exons 3 and 4 of CARD14. A de novo mutation in CARD14, c.413A>C [p.Glu138Ala], was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes compared to wildtype CARD14. These included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, while in lesional psoriatic skin it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the lesional epidermis. We propose that, following a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration that is the hallmark of psoriasis.
2012-05-09 | GSE36387 | GEO
Project description:Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding an NF-kB activator within skin epidermis, account for PSORS2. Here we describe fifteen additional rare, missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There was an excess of rare variants within CARD14 in cases versus controls (burden test p-value = 0.0015). Some variants were only seen in a single case and included putative pathogenic mutations (c.424G>A [p.Glu142Lys], c.425A>G [p.Glu142Gly]) and the generalized pustular psoriasis mutation, c.413A>C (p.Glu138Ala), that lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities, with putative pathogenic variants leading to levels >2.5-fold higher than wildtype CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with TNF-a to achieve significant increases in NF-kB levels. Transcriptome profiling of wildtype and variant CARD14 transfectants in keratinocytes differentiated likely pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped and meta-analysis revealed association of psoriasis with rs11652075 (c.2458C>T/p.Arg820Trp; p-value = 2.1x10-6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.
2012-05-09 | GSE36381 | GEO
Project description:CARD14 gene mutations have been shown to be a causitive factor for psoriasis in human patients. CARD14 signalling is poorly understood and very little is known about how it regulates NF-kB activation. Basic research is therefore required to better understand the mechanisms by which is brings about pathology in a gain-of-function state. Analyses of CARD14 mutant versus WT transcription over time in a relevant cell type (keratinocyte) was pursued as one of several means to better understand CARD14-driven psoriasis.
2024-04-01 | GSE200493 | GEO
Project description:CARD14 is an intracellular NF-κB signaling mediator in the skin, and rare CARD14 variants have been associated with psoriasis and atopic dermatitis. CARD14 is also expressed in intestinal epithelial cells (IEC). However, its function in the intestine remains unknown. We demonstrate here that transgenic mice expressing the psoriasis associated gain-of-function human CARD14(E138A) mutant specifically in IEC, show mild intestinal inflammation, without epithelial damage. Moreover, CARD14(E138A)IEC mice show a drastic reduction in intestinal motility, often associated with rectal prolapse. Enteric neuronal survival and functionality is unaffected in CARD14(E138A)IEC mice. Transcriptome analysis of IEC from CARD14(E138A)IEC mice reveals decreased expression of antimicrobial peptides by Paneth cells, accompanied with microbial dysbiosis and increased susceptibility to enteric bacterial infection. Our findings suggest that gain-of-function CARD14 mutations may not only predispose patients to psoriasis, but also mild intestinal inflammation, reduced intestinal motility and increased sensitivity to intestinal infection. CARD14(E138A)IEC mice are a valuable tool for further investigation of IEC-intrinsic molecular processes involved in intestinal inflammation and motility disorders.
2025-09-17 | GSE302705 | GEO