Visualising the Cross-Level Relationships between Pathological and Physiological Processes and Gene Expression: Analyses of Haematological Diseases

Ono, M.; Tanaka, Reiko; Kano, Manabu; Sugiman, Toshio

doi:10.1371/journal.pone.0053544

Cited by 12 publications

(19 citation statements)

References 60 publications

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“…Next, we analysed gene profiles using a multidimensional analysis. Previous studies have shown how canonical correspondence analysis (CCA) can be applied to genomic data in order to visualise and reveal relationships between experimental samples and specified biological processes 24 . In the present study, CCA visualised transcriptomic similarities between thymic populations (WT thymic populations (DP2, DP3 and HSA hi CD4 SP) and DP3 from chimeras (MhcI KO TetZap70 or TetZap70 fed dox for 3 days)) and their relationships to thymic maturation and development from pre‐selection DP1 to either CD4 or CD8 lineages (Figure 8b).…”

Section: Resultsmentioning

confidence: 99%

“…CCA was performed as described previously, using R and Bioconductor package vegan 24 . Briefly, comparison of transcriptomes of CD8 SP and DP1 thymocytes were used to identify gene expression changes associated with selection and maturation of thymocytes, whereas comparison of CD4 SP HSA lo and CD8 SP thymocytes was used to define changes associated with CD4 vs CD8 lineage specification.…”

Section: Methodsmentioning

confidence: 99%

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A Zap70‐dependent feedback circuit is essential for efficient selection of CD4 lineage thymocytes

2015

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During positive selection of CD4(+), CD8(+) double positive (DP) thymocytes, expression of the tyrosine kinase Zap70 is subject to developmental regulation. Signalling downstream of T-cell receptor (TCR) induces Zap70 expression, forming a positive feedback circuit. Although previous studies show this circuit is required for generation of CD8 lineage cells, it is not known whether selection of CD4 T cells also depends on intact developmental regulation of Zap70. To address this, we analysed development of Class II-restricted thymocytes in mice lacking the Zap70 transcriptional circuitry. Rescue of Zap70 expression in Zap70(-/-) mice using a tetracycline-inducible Zap70 transgene, that is not subject to positive feedback by TCR signalling, restored positive selection of Class-II-restricted thymocytes. However, in conditions of static Zap70 expression, approximately half of selecting thymocytes failed to commit normally to the CD4 lineage. Instead, cells that failed to develop into CD4 T cells resembled CD8 lineage precursor DP thymocytes but failed to survive in vivo. Therefore, the Zap70 feedback circuit is essential to efficiently mediate the CD4 lineage differentiation programme in response to Class II selecting ligands.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A Zap70‐dependent feedback circuit is essential for efficient selection of CD4 lineage thymocytes

2015

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“…Detailed methodology is described elsewhere. 26 Signaling pathway impact analysis was performed using the Bioconductor package, SPIA , by comparing WT and RAG-1 −/− .…”

Section: Methodsmentioning

confidence: 99%

CD4+ but not CD8+ T cells revert the impaired emotional behavior of immunocompromised RAG-1-deficient mice

et al. 2013

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An imbalanced immune system has long been known to influence a variety of mood disorders including anxiety, obsessive-compulsive disorders and depression. In this study, we sought to model the impact of an immunocompromised state on these emotional behaviors using RAG-1−/− mice, which lack T and B cells. We also investigated the relative contribution of CD4+ or CD8+ T cells to these manifestations using RAG-1−/−/OT-II and RAG-1−/−/OT-I transgenic mice, respectively. Our results show that RAG-1−/− mice present a significant increase in digging and marble-burying activities compared with wild-type mice. Surprisingly, these anxiety-like behaviors were significantly reverted in RAG-1−/−/OT-II but not RAG-1−/−/OT-I transgenic mice. Immunodepletion experiments with anti-CD4 or anti-CD8 in C57/BL6 mice or repopulation studies in RAG-1−/− mice did not reproduce these findings. Microarray analysis of the brain of RAG-1−/− and RAG-1−/−/OT-II mice revealed a significantly different gene fingerprint, with the latter being more similar to wild-type mice than the former. Further analysis revealed nine main signaling pathways as being significantly modulated in RAG-1−/− compared with wild-type mice. Taken together, these results suggest that life-long rather than transient immunodeficient conditions influence the emotional behaviors in mice. Most interestingly, these effects seem to correlate with a specific absence of CD4+ rather than CD8+ T cells. Validation of these findings in man might provide new clues on the mechanism by which early life immune modulation might impact mood response in adults and provide a further link between immune and emotional well-being.

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“…23-25 and Figure 1A). The application of canonical correspondence analysis (CCA) to microarray data has recently been reported (26). This method permits the interrogation of transcriptomic data, in the context of a specific biological problem, using another transcriptome as explanatory data.…”

Section: Islet-specific T Cells In the Pancreatic Ln Show A Tfh Gene mentioning

confidence: 99%

“…Quality control was done by the Bioconductor package, affyQCReport. CCA was performed as previously described (26). Briefly, logged expression values of the diabetes T cell data set were analyzed by CCAM using fold change of Tfh and naive Tfh data set (Gene Expression Omnibus [GEO] accession no.…”

Section: Cd45ramentioning

confidence: 99%

Follicular helper T cell signature in type 1 diabetes

Kenefeck¹,

Wang²,

Kapadi³

et al. 2014

J. Clin. Invest.

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by negative magnetic separation (EasySep Human Naive CD4 + T cell Enrichment Kit, Stem Cell Technologies). Cells were plated at a density of 100,000 per well in a 96-well round bottom plate and stimulated with anti-CD3/28 beads (Human T-Activator Dynabeads, Life Technologies) for 5 days. Where indicated, cultures were treated with 10 ng/ml IL-12 and/or 20 ng/ml IL-2 (both from Peprotech). Statistics. Data were analyzed using Prism statistical software. Statistical significance was assessed using the Mann-Whitney test. Paired data were analyzed using a 2-tailed paired Student's t test. A P value of less than 0.05 was considered significant.

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Visualising the Cross-Level Relationships between Pathological and Physiological Processes and Gene Expression: Analyses of Haematological Diseases

Cited by 12 publications

References 60 publications

A Zap70‐dependent feedback circuit is essential for efficient selection of CD4 lineage thymocytes

A Zap70‐dependent feedback circuit is essential for efficient selection of CD4 lineage thymocytes

CD4+ but not CD8+ T cells revert the impaired emotional behavior of immunocompromised RAG-1-deficient mice

Follicular helper T cell signature in type 1 diabetes

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