Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

RNA-seq analysis of IMQ-treated wt and Trex2-/- skin

ABSTRACT: TREX2 is a keratinocyte specific 3â-deoxyribonuclease that participates in the maintenance of skin homeostasis upon damage. This transcriptome analysis identified multiple genes and pathways deregulated by TREX2 loss in the IMQ-induced psoriasis-like model in mouse skin. mRNA sequencing of 5 biological replicates of skin from wild-type mice treated with Imiquimod and 6 of Trex2 knockout mice treated with Imiquimod

ORGANISM(S): Mus musculus

SUBMITTER: Eduard Casas

PROVIDER: E-GEOD-74528 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The Exonuclease Trex2 Shapes Psoriatic Phenotype.

Manils Joan J Casas Eduard E Viña-Vilaseca Arnau A López-Cano Marc M Díez-Villanueva Anna A Gómez Diana D Marruecos Laura L Ferran Marta M Benito Carmen C Perrino Fred W FW Vavouri Tanya T de Anta Josep Maria JM Ciruela Francisco F Soler Concepció C

The Journal of investigative dermatology 20160627 12

Trex2 is a keratinocyte-specific 3'-deoxyribonuclease that participates in the maintenance of skin homeostasis after DNA damage. Here, we show that this exonuclease is strongly upregulated in human psoriasis, a hyperproliferative and inflammatory skin disease. Similarly, the imiquimod (IMQ)- and Il23-induced mouse psoriasis was associated with a substantial upregulation of Trex2, which was recruited into fragmented chromatin in keratinocytes that were undergoing impaired proliferation, different ...[more]

PMID: 27365293

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Project description:Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis. Global transcriptional profiling was utilized to evaluate the similarity between human psoriasis and the psoriasis-like phenotypes that develop in five mouse models (K5-Tie2, IMQ, K14-AREG, K5-Stat3C, K5-TGFbeta1) Expression patterns associated with mouse phenotypes were evaluated by comparing lesional skin from transgenic or IMQ-treated mice (n = 2-3) with normal skin obtained from control mice (n = 2-3).

Project description:Within the regulatory framework on the approval of new substances, the assessment of immunotoxic modes of action (MoA) is currently not covered. This is not least due to the lack of standardized methods and reliable validated biomarkers for immunotoxic effects. The experimental set up was designed to analyze the compound-specific response of zebrafish embryos to two immunomodulative reference substances, clobetasol propionate (CP, CAS 25122-46-7) and imiquimod (IMQ, CAS 99011-02-6), on the global level of gene expression. The obtained results were used to (i) identify potential biomarker candidates for the assessment of immunotoxic MoAs, (ii) identify compound-specific molecular signatures, (iii) evaluate the reliability of data acquisition using OMICs-coupled approaches and (iv) to assess the suitability of the zebrafish embryo as an alternative model for the human-representative investigation of psoriatic effects. For this, the transcriptomic profiles of embryos were bioinformatically analysed subsequent to an CP-induced immunosuppression in absence or presence of an IMQ-induced immune challenge, i.e. the simulation of a resting and an activated immune system. In a modified version of the zebrafish embryo toxicity test (OECD 236), 15 fertilized eggs were exposed to either CP (250 nM) or to IMQ (4000 nM) or to a combination of both under semi static conditions. Exposure to CP started at 2 hours post fertilization (hpf) until 72 hpf. Exposure to IMQ started at 48 hpf until 72 hpf. Untreated embryos reared in medium without CP nor IMQ dissolved was used as a negative control. All conditions comprised three biological replicates. Medium was exchanged on a daily basis by renewing half its volume. Occurrence of morphological changes and indicators of lethality as described in the OECD test guideline 236 were examined microscopically on a daily basis. At 72 hpf, all larvae were pooled for each sample for RNA extraction using a NucleoSpin RNA/Protein kit (Macherey-Nagel) following the manufacturer’s protocol. RNA quality was assessed with a 2100 Bioanalyzer system (Agilent) before coding RNA was purified (PolyA selection with TruSeq RNA Library Prep Kit v2) and sequenced on an Illumina NovaSeq 6000 System (Illumina) in 150 bp paired-end mode, producing a minimum of 30 million reads per sample. Adapter sequences were removed with trimmomatic and sequences were aligned to the Danio rerio reference genome GRCz11 with STAR. Counting of feature mapped reads was performed through featureCounts. Library gene count tables were then merged to a single count matrix as input for differential gene expression analysis with DESeq2.

Dataset Information

RNA-seq analysis of IMQ-treated wt and Trex2-/- skin

Publications

The Exonuclease Trex2 Shapes Psoriatic Phenotype.

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