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Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE71999 | GEO | 2015/08/13

SECONDARY ACCESSION(S): PRJNA292696

REPOSITORIES: GEO

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Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma

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

2015-08-13 | E-GEOD-71999 | biostudies-arrayexpress

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

2015-08-13 | GSE71998 | 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 (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:Interspecies Comparative Genomics Identifies Optimal Mouse Models of Scleroderma

| PRJNA292696 | ENA

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

Comparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy.

Project description:The identification of thalidomide-Cereblon-induced SALL4 degradation has brought new understanding for thalidomide embryopathy (TE) differences across species. Some questions, however, regarding species variability, still remain. The aim of this study was to detect sequence divergences between species, affected or not by TE, and to evaluate the regulated gene co-expression in a murine model. Here, we performed a comparative analysis of proteins experimentally established as affected by thalidomide exposure, evaluating 14 species. The comparative analysis, regarding synteny, neighborhood, and protein conservation, was performed in 42 selected genes. Differential co-expression analysis was performed, using a publicly available assay, GSE61306, which evaluated mouse embryonic stem cells (mESC) exposed to thalidomide. The comparative analyses evidenced 20 genes in the upstream neighborhood of NOS3, which are different between the species who develop, or not, the classic TE phenotype. Considering protein sequence alignments, RECQL4, SALL4, CDH5, KDR, and NOS2 proteins had the biggest number of variants reported in unaffected species. In co-expression analysis, Crbn was a gene identified as a driver of the co-expression of other genes implicated in genetic, non-teratogenic, limb reduction defects (LRD), such as Tbx5, Esco2, Recql4, and Sall4; Crbn and Sall4 were shown to have a moderate co-expression correlation, which is affected after thalidomide exposure. Hence, even though the classic TE phenotype is not identified in mice, a deregulatory Crbn-induced mechanism is suggested in this animal. Functional studies are necessary, especially evaluating the genes responsible for LRD syndromes and their interaction with thalidomide-Cereblon.

| S-EPMC8262662 | biostudies-literature

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