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Insights into gene expression profiles induced by Socs3 depletion in Keratinocytes

ABSTRACT: Specific deletion of suppressor of cytokine signaling 3 (Socs3) in keratinocytes can cause severe skin inflammation with infiltration of immune cells, however the molecular mechanisms and key regulatory pathways involved remains poorly understood. To investigate the role of Socs3 in keratinocytes, we generated and analyzed global RNA-Seq profiles in Socs3 conditional knockout (cKO) mice at two different stages (2- and 10- weeks). Over 400 shared genes were found to be significantly regulated at both time points. Two week samples were marked by initial skin barrier dysfunction established by the downregulation of keratin associated genes and upregulation of genes regulating lipid metabolism. Subsequent increase in expression level of multiple chemokines and cytokines at 10 week were observed representing response to skin inflammation caused by the disruption of skin barrier function. A group of activator protein-1 related genes were to found to be highly elevated in Socs3 cKO mice at both time points. This observation was duly validated using qRT-PCR in Socs3 depleted human keratinocyte–derived HaCaT cells. Overall this study reveals an important regulatory dynamics of Socs3 in skin barrier dysfunction.

OTHER RELATED OMICS DATASETS IN: PRJNA374340

ORGANISM(S): Mus musculus

PROVIDER: GSE94743 | GEO | 2018/02/01

REPOSITORIES: GEO

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Project description:Suppressor of cytokine signaling 3 (SOCS3) down-regulates several signaling pathways in multiple cell types, and previous data suggest that SOCS3 may shut off cytokine activation at the early stages of liver regeneration. We developed hepatocyte-specific Socs3 knockout (Socs3 h-KO) mice to directly study the role of SOCS3 during liver regeneration after 2/3 partial hepatectomy (PH). Socs3 h-KO mice demonstrate marked enhancement of DNA replication and liver weight restoration after 2/3 PH in comparison with littermate controls. Without SOCS3, signal transducer and activator of transcription 3 (STAT3) phosphorylation is prolonged, and activation of the mitogenic kinases extracellular signal-regulated kinase 1/2 (ERK1/2) is enhanced after PH. In vitro, we show that SOCS3 deficiency enhances hepatocyte proliferation in association with enhanced STAT3 and ERK activation after epidermal growth factor (EGF) or interleukin 6 (IL-6) stimulation. Microarray analyses show that SOCS3 modulates a distinct set of genes after PH, which fall into diverse physiologic categories. Using a model of chemical-induced carcinogenesis, we found that Socs3 h-KO mice develop hepatocellular carcinoma (HCC) at an accelerated rate. By acting on cytokines and multiple proliferative pathways, SOCS3 modulates both physiologic and neoplastic proliferative processes in the liver, and may act as a tumor suppressor. Experiment Overall Design: Hepatocyte-specific excision of the Socs3 gene was achieved by breeding Socs3 fl/fl mice with mice expressing the Cre recombinase transgene under control of the albumin promoter (Alb-Cre+), yielding Socs3 h-KO mice. Socs3 fl/fl, Alb-Cre- littermates were used as controls for all experiments, and are henceforth referred to as littermates. All mice (C57BL/6) were free of Helicobacter species, housed in a specific pathogen free facility with 12-h light/dark cycles with free access to standard food and water. 2/3 PH and sham operations were performed as previously described (15, 50) (n=3-6 mice per genotype per time point). Liver remnants were weighed after removal of necrotic stumps and sutures, and compared to post-operative body weight. For HCC experiments, a single i.p. injection of DEN (5mg/kg, Sigma) was performed 12-14 d after birth. For short time points, a single injection of DEN (100mg/kg) (31) was given to 4 wk old mice. At indicated time points, mice were sacrificed by CO2 inhalation. All animal studies were carried out under approved IACUC protocols at the University of Washington.

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Insights into gene expression profiles induced by Socs3 depletion in Keratinocytes

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