Comparative analysis of gene expression in the skin of WT and LynDeltaN mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE12722 | GEO | 2009/06/01
SECONDARY ACCESSION(S): PRJNA112661
REPOSITORIES: GEO
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Project description:To examine the interaction between LYN kinase and BRCA1 loss-of-function in an in vivo mouse mammary tumour model, we have used conditional knockout Brca1 and Lyn alleles targeted to the mammary epithelium, on a p53 heterozygote background. Comparison of tumour cohorts demonstrated that homozygous conditional Lyn cohorts developed tumours significantly faster than the other genotypes. Transcriptomic analysis to identify and compare tumours with the highest and lowest Lyn levels from across the cohorts showed that ‘Lyn high’ tumours had a significantly slower doubling time and were enriched in inflammatory pathways and canonical NfkB signalling. ‘Lyn low’ tumours had a faster doubling time and were enriched in PI3K, WNT and NOTCH pathways. Therefore, these results suggest that, in this model at least, LYN acts as a tumour suppressor in the context of Brca1 loss.
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Project description:Rationale: Monocytes are key effectors of the mononuclear phagocyte system (MPS), playing critical roles in regulating tissue homeostasis and coordinating inflammatory reactions, including those involved in chronic inflammatory diseases such as atherosclerosis. Monocytes have traditionally been divided into two major subsets termed conventional (cMo) and patrolling (pMo) monocytes but recent systems immunology approaches have identified marked heterogeneity within these cells, and much of what regulates monocyte population homeostasis remains unknown. We and others have previously identified LYN tyrosine kinase as a key negative regulator of myeloid cell biology, however LYN’s role in regulating specific monocyte subset homeostasis has not been investigated. Objective: We sought to comprehensively profile monocytes in order to elucidate the underlying heterogeneity within monocytes and dissect how Lyn deficiency affects monocyte subset composition, signaling, and gene expression. We further tested the biological significance of these findings in a model of atherosclerosis. Methods and Results: CyTOF analysis of monocyte subsets and signaling pathway activation patterns in cMos and pMos revealed distinct baseline signaling profiles and far greater heterogeneity than previously described. Lyn deficiency led to a selective expansion of pMos and alterations in specific signaling pathways within these cells, revealing a critical role for LYN in pMo physiology. LYN’s role in regulating pMos was cell-intrinsic and correlated with an increased circulating half-life of Lyn-deficient pMos. Furthermore, single cell RNA sequencing revealed marked perturbations in the gene expression profiles of Lyn-/- monocytes with upregulation of genes involved in pMo development, survival, and function. Lyn deficiency also led to a significant increase in aorta-associated pMos and protected Ldlr-/- mice from high-fat diet induced atherosclerosis. Conclusions: Together our data identify LYN as a key regulator of pMo development and a potential therapeutic target in inflammatory diseases regulated by pMos.
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Project description:Previous studies showed that aging in coronary arteries is associated with pro-inflammatory phenotypic changes and decreased NO bioavailability, which, we hypothesized, promotes vascular disease by inducing endothelial apoptosis. To test this hypothesis we characterized pro-apoptotic alterations in the phenotype of coronary arteries of aged (26 month old) and young (3 month old) F344 rats. DNA fragmentation analysis and TUNEL assay showed that in aged vessels there was a ~4 fold increase in the number of apoptotic endothelial cells. Analysis of the expression of apoptosis-related genes (microarray, real-time PCR) showed that in aged coronary arteries there was an increased expression of TNFa, TNFb, caspase 9 and an increased presence of cleaved caspase 3 and caspase 9 (Western blotting), whereas expression of TNFR1 and that of TRADD, Bcl-2, Bcl-X(L), Bid, Bax, caspase 8 and caspase 3 were unchanged. We propose that aging-induced up-regulation of TNFa and decreased bioavailability of NO promote endothelial apoptosis in coronary arteries that may lead to the development of endothelial dysfunction and ischemic heart disease in the elderly. Keywords: repeat sample
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Project description:Psoriasis is a common, immune-mediated, genetic disorder of the skin associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosome 17q25.3-qter following a genome-wide linkage scan in a family of European origin with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a multiply affected psoriasis family from Taiwan. With genomic capture and DNA sequencing, we identified unique gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) that segregated with psoriasis. The mutations, c.349G>A (p.Gly117Ser) and c.349+5G>A respectively, altered splicing between exons 3 and 4 of CARD14. A de novo mutation in CARD14, c.413A>C [p.Glu138Ala], was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes compared to wildtype CARD14. These included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, while in lesional psoriatic skin it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the lesional epidermis. We propose that, following a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration that is the hallmark of psoriasis. No replicates are included. Three sample sets. [1] Skin biopsies had RNA extracted for expression within target tissue. [2] HEK cells were transfected with different constructs (including wildtype) of CARD14 to determine the mutational effect in keratinocytes. [3] Keratinocytes derived from psoriasis patients with CARD14 mutations were cultured and compared with and without stimulation with TNFalpha.
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