Integrated network analysis of transcriptomic and proteomic data in psoriasis

Пирузян, Е. С.; Брускин, С. А.; Ishkin, Alexander; Abdeev, R. M.; Moshkovskii, Sergei A.; Melnik, Stanislav; Nikolsky, Yuri; Nikolskaya, Tatiana

doi:10.1186/1752-0509-4-41

Cited by 62 publications

(55 citation statements)

References 84 publications

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“…The peptides identified were all epidermal derived, with many redox-specific peptides reported. Of particular relevance to the results we present here, was the identification across many studies of psoriasis-associated increases in serine protease inhibitors, Serpins (25)(26)(27).…”

Section: Discussionmentioning

confidence: 78%

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Proteomics of Skin Proteins in Psoriasis: From Discovery and Verification in a Mouse Model to Confirmation in Humans

Lundberg¹,

Fritz

Johnston

et al. 2015

Molecular & Cellular Proteomics

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Herein, we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n ‫؍‬ 3) were compared with littermate controls (n ‫؍‬ 3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes >2.0 including: stefin A1 (average fold change of 342.4 and an average p ‫؍‬ 0.0082; cystatin A, human ortholog); slc25a5 (average fold change of 46.2 and an average p ‫؍‬ 0.0318); serpinb3b (average fold change of 35.6 and an average p ‫؍‬ 0.0345; serpinB1, human ortholog); and kallikrein related peptidase 6 (average fold change of 4.7 and an average p ‫؍‬ 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, p < 0.0001), KLK6 (9-fold, p ‫؍‬ 0.002), stefin A1 (7.3-fold; p < 0.001), and slc25A5 (1.5-fold; p ‫؍‬ 0.05) using qRT-PCR on a second cohort of animals (n ‫؍‬ 8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; p < 0.05), 29,000-fold (stefinA1; p < 0.01), 322-fold (KLK6; p < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes versus healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3-fold), KLK6 (5.8-fold), and serpinB1 (76-fold; all p < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover, slc25a5, cystatin A, KLK6, and serpinB1 protein were all increased in lesional psoriasis skin compared with normal skin. These results highlight the usefulness of preclinical disease models using readily-available mouse skin and demonstrate the utility of proteomic approaches for identifying novel peptides/proteins that are differentially regulated in psoriasis that could serve as sources of autoantigens or provide novel therapeutic targets for the development of new anti-psoriatic treatments. One in three individuals in the United States is afflicted with a skin disease, with ϳ2-3% of the American population suffering from psoriasis (1-3) a chronic, immune-mediated inflammatory skin disease characterized by well-demarcated areas of "involved" red, raised, and scaly skin adjacent to areas of "uninvolved" normal appearing skin. The underlying cause of psoriasis remains unknown and the specific signals that trigger disease onset have yet to be identified; however, several lines of evidence suggest the involvement of antigenspecific T cells, although the antigens involved remain elusive (4). A combination of human and animal studies have led to the understanding that in patients with a genetica...

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Section: Discussionmentioning

confidence: 78%

“…Previous proteomic approaches for studying skin have used both human and mouse tissue (22)(23)(24) and have examined chronic plaque psoriasis (25)(26)(27)). An early manuscript (24) utilized MALDI-TOF to study skin from Balb/c and C3H/ HeN mice in order to identify proteins from different skin regions and different skin compartments.…”

Section: Discussionmentioning

confidence: 99%

Proteomics of Skin Proteins in Psoriasis: From Discovery and Verification in a Mouse Model to Confirmation in Humans

Lundberg¹,

Fritz

Johnston

et al. 2015

Molecular & Cellular Proteomics

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“…Psoriatic samples were clustered on the basis of distinct gene expression patterns identifying two molecular disease subtypes: pathways particularly enriched in one of the two subgroups included transforming growth factor b and ErbB, thus, suggesting putative therapeutic targets for these patients. A network-based methodology has also been used for the integrative analysis of proteomics and transcriptomics data sets identifying similarities and differences between the two levels of cellular organization (Piruzian et al 2010) Moreover, systems biology is used to analyze and visualize the complex connections and multiple levels of biological hierarchies of subcellular processes, such as gene regulatory networks and signal transduction pathways. A systems biology approach has been used to model and quantify immune cell interactions contributing to skin inflammation via cytokine signaling (Valeyev et al 2010).…”

Section: Biomarker Discovery In Psoriasis: State Of the Art And Innovmentioning

confidence: 99%

Psoriasis

Meglio

Villanova

Nestle

2014

Cold Spring Harbor Perspectives in Medicine

267

202

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Psoriasis is a common chronic inflammatory skin disease with a spectrum of clinical phenotypes and results from the interplay of genetic, environmental, and immunological factors. Four decades of clinical and basic research on psoriasis have elucidated many of the pathogenic mechanisms underlying disease and paved the way to effective targeted therapies. Here, we review this progress and identify future directions of study that are supported by a more integrative research approach and aim at further improving the patients' life.This skin is me, I can't get out.

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“…It calculates relative connectivity (number of interactions) of individual genes within the dataset compared with the entire data base based on the comprehensive collection of their known interactions (31). A gene was considered overconnected if it had more direct interactions with the genes of interest than it would be expected by chance (32). The related statistics are described in detail elsewhere (31).…”

Section: Methodsmentioning

confidence: 99%

Interorgan Coordination of the Murine Adaptive Response to Fasting

Hakvoort

Moerland

Frijters

et al. 2011

Journal of Biological Chemistry

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Starvation elicits a complex adaptive response in an organism.No information on transcriptional regulation of metabolic adaptations is available. We, therefore, studied the gene expression profiles of brain, small intestine, kidney, liver, and skeletal muscle in mice that were subjected to 0 -72 h of fasting. Functional-category enrichment, text mining, and network analyses were employed to scrutinize the overall adaptation, aiming to identify responsive pathways, processes, and networks, and their regulation. The observed transcriptomics response did not follow the accepted "carbohydrate-lipid-protein" succession of expenditure of energy substrates. Instead, these processes were activated simultaneously in different organs during the entire period. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, and by increased proteolysis in the muscle. The brain was extremely well protected from the sequels of starvation. 60% of the identified overconnected transcription factors were organ-specific, 6% were common for 4 organs, with nuclear receptors as protagonists, accounting for almost 40% of all transcriptional regulators during fasting. The common transcription factors were PPAR␣, HNF4␣, GCR␣, AR (androgen receptor), SREBP1 and -2, FOXOs, EGR1, c-JUN, c-MYC, SP1, YY1, and ETS1. Our data strongly suggest that the control of metabolism in four metabolically active organs is exerted by transcription factors that are activated by nutrient signals and serves, at least partly, to prevent irreversible brain damage.Adapting to starvation requires an interorgan integration of the activity of metabolic pathways to protect the body from an irreversible loss of resources (1, 2), but how the organism integrates these reactions remains largely unknown. Numerous studies on humans, who fasted for 3-6 weeks, have shown that glycogen stores are depleted within a day (3). The decline in circulating glucose and insulin during the next few days (4) induces a transient increase in plasma (essential) amino acids and a concomitant decline in plasma alanine levels due to an increased hepatic extraction for gluconeogenesis (5, 6). Muscle catabolism is a major source of amino acids in this phase. When fasting is continued, muscle protein catabolism declines, and hepatic uptake of amino acids decreases, which is reflected in a decline of endogenous glucose production (6) and urinary nitrogen excretion (4, 7). Lipid catabolism and the (hepatic) production of ketone bodies also increases rapidly and is quantitatively similar after 3 days and 5-6 weeks of starvation (8), but plasma levels increase only gradually to plateau after 4 weeks (4, 9). The associated increase in urinary ketone body (organic-acid) excretion requires a compensatory increase in ammonia production and urinary excretion (4, 7, 10), which is met by an increased renal amino acid uptake and gluconeogenesis (5, 6)...

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Integrated network analysis of transcriptomic and proteomic data in psoriasis

Cited by 62 publications

References 84 publications

Proteomics of Skin Proteins in Psoriasis: From Discovery and Verification in a Mouse Model to Confirmation in Humans

Proteomics of Skin Proteins in Psoriasis: From Discovery and Verification in a Mouse Model to Confirmation in Humans

Psoriasis

Interorgan Coordination of the Murine Adaptive Response to Fasting

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