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Comparative transcriptomic analysis of WT and XP-C fibroblasts cultured in 3D-dermal equivalents

ABSTRACT: Xeroderma Pigmentosum (XP) is a rare autosomal genetic disease. XP patients present a default in the mechanism responsible for the repair of UV-induced DNA lesions. They are prone to develop skin cancers with high frequencies early in their life. To identify microenvironment factors that could contribute to the progression of skin cancers in XP-C group we did comparative transcriptomic analysis of WT and XP-C dermal patient’s fibroblasts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133084 | GEO | 2019/09/19

REPOSITORIES: GEO

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Expression data from Healty Control and XP-A melanocytes

Project description:Xeroderma Pigmentosum (XP) is a DNA repair disorder characterized by photosensitivity, resulting in occurrence of freckle-like pigmented maculae and depigmented maculae on sun-exposed areas. XP complementation group A (XP-A) is the most frequent type in Japan, and patients with XP-A present most severe cutaneous and neurological symptoms due to nucleotide excision repair deficiency. Here, we established induced pluripotent stem cells (iPSCs) derived from XP-A patients and successfully differentiated into melanocytes. To elucidate the pathophysiology of XP, we comprehensively analyzed the difference in gene expression between XP-A-iMCs and healthy-control-iPSC-derived melanocytes (HC-iMCs) 4 hours and 12 hours after irradiation with 30 J/m2 or 150 J/m2 of UV-B using microarray analysis.

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Cxcl1 antagonist on UVB-induced skin inflammation leading to inhibitory effects on photo-skin tumorigensis in Xeroderma pigmentosum type A deficient mice

Project description:Xeroderma pigmentosum type A (XP-A) is a hereditary disease characterized by early onset of skin cancers development by ultraviolet (UV) exposure. Although etiology of susceptible to skin tumor of XP-A is well investigated as a repair deficiency by UV-induced DNA damage, the mechanism of unusual strong and prolonged skin inflammation caused by UV in XP-A and whether UV-induced inflammatory response relates to skin tumor-prone phenotype remains to be elucidated. Among up-regulated inflammatory response related genes in Xpa mice compared with wild-type by gene profiling study, Cxcl1 in Xpa mice was significantly different from wild-type and blood level of Cxcl1 was increased with UVB exposed on even small area of skin in Xpa mice. We administered Cxcl1 neutralizing antibody or antioxidant agent n-acetylcysteine for Xpa mice after UVB irradiation, showing that blood levels of Cxcl1, ear swelling and skin redness as an inflammatory response were significantly suppressed. Xpa mice with chronic UVB exposure and Cxcl1 neutralizing antibody or n-acetylcysteine administered Xpa mice yields much less skin tumors compared with control group. Those results indicate that highly inflammatory response of Xpa mice by UVB plays a role of skin tumor development that could be suppressed by chemokine as Cxcl1 through antioxidant mechanism.

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Expression data from XP-A and XP-V cells after UVC exposure

Project description:XPA is required for Nucleotide Excision Repair system, which could function to repair DNA damage induced by the UV. UV damage on the genomic DNA cannot be removed, thus persistence of damage could affect the transcriptional machinary. We used the microarray to investigate the global expression profiles in the XP-A and XP-V cells in the low dose of UVC comparing with fibroblast from healthy person. Human primary fibroblasts were developed from the skin of healthy person and two XP patients (XP-A and XP-V). We evaluated global expression profiles comparing the UVC-exposed (0.5J/m2, 5J/m2) with non-exposed sample.

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Project description:Xeroderma pigmentosum (XP) is caused by defective nucleotide excision-repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We show substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find that the endoplasmic reticulum stress response is upregulated and reversal of the mutant genotype is associated with phenotypic rescue. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity in XP neuronal models improves phenotypes, albeit inadequately. Although more work is required, this study presents insights with intervention potential.

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Expression data from XP-A and XP-V cells after UVC exposure

2015-07-14 | GSE70818 | GEO

A disease-associated XPA allele interferes with TFIIH binding and primarily affects the transcription-coupled sub-pathway of nucleotide excision repair

Project description:XPA is a central scaffold protein in nucleotide excision repair (NER) that interacts with and coordinates the assembly of repair complexes. Inactivating mutations in XPA causes Xeroderma Pigmentosum (XP), which is characterized by extreme UV sensitivity and a highly elevated skin cancer risk. Here, we describe two Dutch siblings in their late forties carrying a homozygous H244R substitution in the C-terminus of XPA with a mild manifestation of XP without skin cancer, but with neurological features including cerebellar ataxia. We show that the mutant XPA protein shows a severely weakened interaction with the TFIIH complex leading to its inefficient association with NER complexes and an inability to support the efficient association of the ERCC1-XPF endonuclease with repair complexes. Despite these defects, we find that patient-derived fibroblasts and reconstituted knockout cells carrying the H244R substitution show considerable levels of residual global genome repair (~40%), which is in intrinsic property of the mutated protein as revealed by in vitro experiments. In contrast, patient fibroblasts and engineered cells only expressing the mutant XPA protein were fully deficient in transcription-coupled repair. We report a new case of XPA deficiency that interferes with TFIIH binding and primarily affects the transcription-coupled sub-pathway of nucleotide excision repair, which is more closely associated with neurological features than to skin abnormalities.

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Project description:XP Raw sequence reads

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GENOMIC MUTATION LANDSCAPE OF SKIN CANCERS FROM DNA REPAIR-DEFICIENT XERODERMA PIGMENTOSUM PATIENTS

Project description:Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis (TLS) DNA polymerase ÃŽÂ· (group V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyzed 38 skin cancer genomes from five XP groups. We found that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors revealed the role of polymerase ÃŽÂ· in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3Ã¢Â€Â™ nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population.

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Project description:Embryonic stem cells can self-renew and differentiate, holding great promise for regenerative medicine. They also employ multiple mechanisms to preserve the integrity of their genomes. Nucleotide excision repair, a versatile repair mechanism, removes bulky DNA adducts from the genome. However, the dynamics of the capacity of nucleotide excision repair during stem cell differentiation remain unclear. Here, using immunoslot blot assay, we measured repair rates of UV-induced DNA damage during differentiation of human embryonic carcinoma (NTERA-2) cells into neurons and muscle cells. Our results revealed that the capacity of nucleotide excision repair increases as cell differentiation progresses. We also found that inhibition of the apoptotic signaling pathway has no effect on nucleotide excision repair capacity. Furthermore, RNA-seq-based transcriptomic analysis indicated that expression levels of four core repair factors, xeroderma pigmentosum (XP) complementation group A (XPA), XPC, XPG, and XPF-ERCC1, are progressively up-regulated during differentiation, but not those of replication protein A (RPA) and transcription factor IIH (TFIIH). Together, our findings reveal that increase of nucleotide excision repair capacity accompanies cell differentiation, supported by the up-regulated transcription of genes encoding DNA repair enzymes during differentiation of two distinct cell lineages.

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