Comparison of Zmiz1-induced keratoancanthoma and normal skin
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE39360 | GEO | 2012/10/01
SECONDARY ACCESSION(S): PRJNA170737
REPOSITORIES: GEO
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Project description:Transgenic mice expressing a truncated form of Zmiz1 in the skin develop spontaneous keratoacanthomas. In this experiment, a Cre-inducible transgene expressing a truncated form of Zmiz1 was introduced into mice. Activation of the transgene in these mice was achieved by breeding to K14-Cre transgenic animals. Double transgenic mice formed spontaenous keratoacanthomas with short latency. In this experiment, we generated gene expression profiles for five Zmiz1-induced keratoacanthomas and six normal skin samples.
2012-10-01 | E-GEOD-39360 | biostudies-arrayexpress
Project description:The homeostasis of both cornea and hair follicles depends on a constant supply of progeny cells produced by populations of keratin (K) 14-expressing stem cells localized in specific niches. To investigate the potential role of Co-factors of LIM domains (Clims) in such tissues, we generated transgenic mice expressing a dominant-negative Clim molecule (DN-Clim) under the control of the K14 promoter. As expected, the K14 promoter directed high level expression of the transgene to the basal cells of cornea and epidermis, as well as the outer root sheath of hair follicles. In corneal epithelium, the transgene expression causes decreased expression of adhesion molecule BP180 and defective hemidesmosomes, leading to detachment of corneal epithelium from the underlying stroma, which in turn causes blisters, wounds and an inflammatory response. After a period of epithelial thinning, the corneal epithelium undergoes differentiation to an epidermis-like structure. The K14-DN-Clim mice also develop progressive hair loss due to dysfunctional hair follicles that fail to generate hair shafts. The number of hair follicle stem cells is decreased by at least 50% in K14-DN-Clim mice, indicating that Clims are required for hair follicle stem cell maintenance. We hypothesize that Clim2 is an essential co-factor for the LIM homeodomain factor Lhx2, which was previously shown to play a role in hair follicle stem cell maintenance. Together, these data indicate that Clim proteins play important roles in the homeostasis of corneal epithelium and hair follicles. Keywords: Comparison of wild-type and transgenic skin tissue
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Project description:The most recurrently mutated oncogene in T-cell acute lymphoblastic leukemia (T-ALL) is NOTCH1. The core Notch complex consists of an ICN protein, a Maml cofactor, and the DNA binding factor Rbpj. The known direct cofactors of Notch appear to act nonselectively, homogeneously driving Notch gene expression functions. It is unclear whether there are direct cofactors of Notch that act selectively and heterogeneously regulate ICN. We discovered that Zmiz1, a Protein Inhibitor of Activated STAT (PIAS)-like coactivator, directly bound ICN1. ChIP-Seq showed that Zmiz1 selectively co-bound only a subset of Notch-regulated enhancers. This led to hypothesize that Zmiz1 regulates only a subset of Notch1 target genes. To investigate this, we performed RNA-Seq on four 8946 cell linesin which L1601P (activated Notch1) or Zmiz1 were expressed alone or in combination. Zmiz1 induced ~10% of Notch target genes. The Notch target gene that was most strongly induced by Zmiz1 was Myc. Our data suggest that Zmiz1 selectively amplifies a subset of Notch target genes with strong amplification of Myc. RNA-Seq in a murine T-ALL cell line
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Project description:The most recurrently mutated oncogene in T-cell acute lymphoblastic leukemia (T-ALL) is NOTCH1. The core Notch complex consists of an ICN protein, a Maml cofactor, and the DNA binding factor Rbpj. The known direct cofactors of Notch appear to act nonselectively, homogeneously driving Notch gene expression functions. It is unclear whether there are direct cofactors of Notch that act selectively and heterogeneously regulate ICN. We discovered that Zmiz1, a Protein Inhibitor of Activated STAT (PIAS)-like coactivator, directly bound ICN1. In order to determine whether this interaction occured at chromatin, we performed ChIP-Seq. We identified significant overlap between ICN1, Rbpj, and Zmiz1 peaks. 75% of overlapping ICN1/Rbpj peaks overlapped with Zmiz1 (HA) peaks (273 peaks). The size of Zmiz1 (HA) peaks had moderate correlation with the size of Rbpj and ICN1 peaks. Like Rbpj and ICN1 peaks, Zmiz1 (HA) peaks were associated with activating H3K27ac, H3K4me1, and H3K4me3 chromatin marks and were devoid of repressive H3K27me3 marks. These data suggest that Zmiz1 is a selective Notch regulator. It co-binds only a subset of ICN1 and Rbpj-regulated sites. Zmiz1, ICN1, Rbpj, histone mehylation ChIP-Seq in murine T-ALL cell line
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Project description:The homeostasis of both cornea and hair follicles depends on a constant supply of progeny cells produced by populations of keratin (K) 14-expressing stem cells localized in specific niches. To investigate the potential role of Co-factors of LIM domains (Clims) in such tissues, we generated transgenic mice expressing a dominant-negative Clim molecule (DN-Clim) under the control of the K14 promoter. As expected, the K14 promoter directed high level expression of the transgene to the basal cells of cornea and epidermis, as well as the outer root sheath of hair follicles. In corneal epithelium, the transgene expression causes decreased expression of adhesion molecule BP180 and defective hemidesmosomes, leading to detachment of corneal epithelium from the underlying stroma, which in turn causes blisters, wounds and an inflammatory response. After a period of epithelial thinning, the corneal epithelium undergoes differentiation to an epidermis-like structure. The K14-DN-Clim mice also develop progressive hair loss due to dysfunctional hair follicles that fail to generate hair shafts. The number of hair follicle stem cells is decreased by at least 50% in K14-DN-Clim mice, indicating that Clims are required for hair follicle stem cell maintenance. We hypothesize that Clim2 is an essential co-factor for the LIM homeodomain factor Lhx2, which was previously shown to play a role in hair follicle stem cell maintenance. Together, these data indicate that Clim proteins play important roles in the homeostasis of corneal epithelium and hair follicles. Experiment Overall Design: We profiled mRNA expression in mouse back skin from 3 time points, representing the initial hair follicle morphogenesis (P6 and P14) and the first telogen (P23); hair growth is synchronized during these time points. For each time point, RNA was isolated and analyzed from 3 to 5 transgenic mice and same number of wild-type littermates.
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