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Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Michael Whitfield

PROVIDER: E-GEOD-71999 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma (Tsk1/+)

Project description:Systemic sclerosis (SSc) is confounded by considerable disease heterogeneity. Animal models of SSc that recapitulate distinct subsets of disease at the molecular level have not delineated. We applied interspecies comparative analysis of genomic data from multiple mouse models of SSc and patients with SSc to determine which animal models best reflect the SSc intrinsic gene expression subsets. Gene expression measured in skin from mice with sclerodermatous graft-versus-host disease, bleomycin-induced fibrosis, or Tsk1/+ and Tsk2/+ mice was mapped to human orthologs and compared to SSc skin biopsy-derived gene expression.

2015-08-13 | E-GEOD-71991 | biostudies-arrayexpress

Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma (Tsk2)

2015-08-13 | E-GEOD-71995 | biostudies-arrayexpress

Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma (bleoskin)

2015-08-13 | E-GEOD-71998 | biostudies-arrayexpress

Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-08-13 | GSE71999 | GEO

Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma (Tsk2)

2015-08-13 | GSE71995 | GEO

Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma (Tsk1/+)

2015-08-13 | GSE71991 | GEO

Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma (bleoskin)

2015-08-13 | GSE71998 | GEO

Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma

Project description:Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma

| PRJNA292696 | ENA

The Tsk2/+ mouse fibrotic phenotype is due to a gain-of-function mutation in the PIIINP segment of the Col3a1 gene

Project description:Systemic sclerosis (SSc) is a polygenic, autoimmune disorder of unknown etiology, characterized by the excessive accumulation of extracellular matrix (ECM) proteins, vascular alterations, and autoantibodies. The tight skin (Tsk)2/+ mouse model of SSc demonstrates signs similar to SSc including tight skin and excessive deposition of dermal ECM proteins. By linkage analysis, we mapped the Tsk2 gene mutation to less than 3 megabases on chromosome 1. We performed both RNA sequencing of skin transcripts and genome capture DNA sequencing of the region spanning this interval in Tsk2/+ and wild-type littermates. A missense point mutation in the procollagen III amino terminal propeptide segment (PIIINP) of Col3a1 was found to be the best candidate for Tsk2, so both in vivo and in vitro genetic complementation tests were used to prove that this Col3a1 mutation is the Tsk2 gene. All previously documented mutations in the human Col3a1 gene are associated with Ehlers-Danlos syndrome, a connective tissue disorder that leads to a defect in type III collagen synthesis. The Tsk2 point mutation is the first documented gain-of-function mutation associated with Col3a1, which leads instead to fibrosis. This discovery provides insight into the mechanism of skin fibrosis manifested by Tsk2/+ mice. For the transfection experiment, three Col3a1 knockout fibroblast transfected with WT Col3a1 samples and three Col3a1 knockout fibroblast transfected with Tsk2 Col3a1 samples were used. For the 4-week female, three WT mice and three Tsk2 total skin RNA were used.

2015-09-24 | E-GEOD-61728 | biostudies-arrayexpress

Identification of Optimal Mouse Models of Systemic Sclerosis by Interspecies Comparative Genomics.

Project description:ObjectiveUnderstanding the pathogenesis of systemic sclerosis (SSc) is confounded by considerable disease heterogeneity. Animal models of SSc that recapitulate distinct subsets of disease at the molecular level have not been delineated. We applied interspecies comparative analysis of genomic data from multiple mouse models of SSc and patients with SSc to determine which animal models best reflect the SSc intrinsic molecular subsets.MethodsGene expression measured in skin from mice with sclerodermatous graft-versus-host disease (GVHD), bleomycin-induced fibrosis, Tsk1/+ or Tsk2/+ mice was mapped to human orthologs and compared to SSc skin biopsy-derived gene expression. Transforming growth factor β (TGFβ) activation was assessed using a responsive signature in mice, and tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression was measured in SSc patient and mouse skin.ResultsGene expression in skin from mice with sclerodermatous GVHD and bleomycin-induced fibrosis corresponded to that in SSc patients in the inflammatory molecular subset. In contrast, Tsk2/+ mice showed gene expression corresponding to the fibroproliferative SSc subset. Enrichment of a TGFβ-responsive signature was observed in both Tsk2/+ mice and mice with bleomycin-induced skin fibrosis. Expression of TNFRSF12A (the TWEAK receptor/fibroblast growth factor-inducible 14) was elevated in skin from patients with fibroproliferative SSc and the skin of Tsk2/+ mice.ConclusionThis study reveals similarities in cutaneous gene expression between distinct mouse models of SSc and specific molecular subsets of the disease. Different pathways underlie the intrinsic subsets including TGFβ, interleukin-13 (IL-13), and IL-4. We identify a novel target, Tnfrsf12a, with elevated expression in skin from patients with fibroproliferative SSc and Tsk2/+ mice. These findings will inform mechanistic and translational preclinical studies in SSc.

| S-EPMC5695038 | biostudies-literature

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