Identification of transcriptional regulators in the mouse immune system

Jojic, Vladimir; Shay, Tal; Sylvia, Katelyn; Zuk, Or; Sun, Xin; Kang, Joonsoo; Regev, Aviv; Koller, Daphne

doi:10.1038/ni.2587

Cited by 181 publications

(207 citation statements)

References 38 publications

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“…Of the 81 gene sets defined by ImmGen that are associated with specific classes of immune and nonimmune cell types (coarse modules, as defined in ref. 19), 17 displayed significantly higher expression in catheterized mice compared with naive control animals (P adj < 0.05; corrected for number of modules tested, against the null hypothesis of no overall change in expression; Supplemental Figure 2 and Supplemental Table 5). These modules were associated with specific immune cell lineages, including DCs and granulocytes, consistent with the involvement of biological processes such as cell migration and motility.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, we hypothesized that specific immune cell populations were present in the tissue and that genes associated with these populations would be prominently represented in the differentially expressed genes we observed to be upregulated in the catheterized state. We examined publicly available data from a compendium of immune cell types in C57BL/6J mice collected by the Immunological Genome Project (ImmGen) (19,20) and observed that this was indeed the case. Of the 81 gene sets defined by ImmGen that are associated with specific classes of immune and nonimmune cell types (coarse modules, as defined in ref.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Bladder catheterization increases susceptibility to infection that can be prevented by prophylactic antibiotic treatment

Rousseau¹,

Goh²,

Holec³

et al. 2016

JCI Insight

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International audienceCatheter-associated urinary tract infections (CAUTI) are the most common hospital-associated infections. Here, we report that bladder catheterization initiated a persistent sterile inflammatory reaction within minutes of catheter implantation. Catheterization resulted in increased expression of genes associated with defense responses and cellular migration, with ensuing rapid and sustained innate immune cell infiltration into the bladder. Catheterization also resulted in hypersensitivity to Enterococcus faecalis and uropathogenic Escherichia coli (UPEC) infection, in which colonization was achieved using an inoculum 100-fold lower than the ID90 for infection of an undamaged urothelium with the same uropathogens. As the time of catheterization increased, however, colonization by the Gram-positive uropathogen E. faecalis was reduced, whereas catheterization created a sustained window of vulnerability to infection for Gram-negative UPEC over time. As CAUTI contributes to poorer patient outcomes and increased health care expenditures, we tested whether a single prophylactic antibiotic treatment, concurrent with catheterization, would prevent infection. We observed that antibiotic treatment protected against UPEC and E. faecalis bladder and catheter colonization as late as 6 hours after implantation. Thus, our study has revealed a simple, safe, and immediately employable intervention, with the potential to decrease one of the most costly hospital-incurred infections, thereby improving patient and health care economic outcome

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Bladder catheterization increases susceptibility to infection that can be prevented by prophylactic antibiotic treatment

Rousseau¹,

Goh²,

Holec³

et al. 2016

JCI Insight

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“…Microarray comparisons of gene expression in B-cell subsets have identified Zfp318 as a member of a set of mRNAs that increases during maturation of immature B cells into mature follicular B cells (22)(23)(24). By analyzing flow-sorted B-cell subsets, we confirmed expression of Zfp318 mRNA closely parallels IgD heavy chain (Ighd) mRNA during B-cell development ( Two alternatively spliced isoforms of Zfp318 mRNA are annotated in the genome and described in the literature (18) (Fig.…”

Section: Identification Of a Missense Mutation In Zfp318 Causing Decrmentioning

confidence: 99%

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Enders¹,

Short²,

Miosge³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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IgD and IgM are produced by alternative splicing of long primary RNA transcripts from the Ig heavy chain (Igh) locus and serve as the receptors for antigen on naïve mature B lymphocytes. IgM is made selectively in immature B cells, whereas IgD is coexpressed with IgM when the cells mature into follicular or marginal zone B cells, but the transacting factors responsible for this regulated change in splicing have remained elusive. Here, we use a genetic screen in mice to identify ZFP318, a nuclear protein with two U1-type zinc fingers found in RNA-binding proteins and no known role in the immune system, as a critical factor for IgD expression. A point mutation in an evolutionarily conserved lysine-rich domain encoded by the alternatively spliced Zfp318 exon 10 abolished IgD expression on marginal zone B cells, decreased IgD on follicular B cells, and increased IgM, but only slightly decreased the percentage of B cells and did not decrease expression of other maturation markers CD21, CD23, or CD62L. A targeted Zfp318 null allele extinguished IgD expression on mature B cells and increased IgM. Zfp318 mRNA is developmentally regulated in parallel with IgD, with little in pro-B cells, moderate amounts in immature B cells, and high levels selectively in mature follicular B cells. These findings identify ZFP318 as a crucial factor regulating the expression of the two major antibody isotypes on the surface of most mature B cells.IgHm | IgHd | immunoglobulin isotype |

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“…One notable study examined gene coexpression in a several tissues separately and showed that such a tissue-specific approach was more efficient in predicting disease genes (12). Other efforts, such as the Immunological Genome Project (ImmGen) and ImmuNet, offer data-driven approaches for studying the immune system (13,14). However, low sample counts per cell type in the ImmGen dataset prohibit analysis of cell typespecific correlation of expression.…”

mentioning

confidence: 99%

Immuno-Navigator, a batch-corrected coexpression database, reveals cell type-specific gene networks in the immune system

Vandenbon

Dinh

Mikami

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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High-throughput gene expression data are one of the primary resources for exploring complex intracellular dynamics in modern biology. The integration of large amounts of public data may allow us to examine general dynamical relationships between regulators and target genes. However, obstacles for such analyses are studyspecific biases or batch effects in the original data. Here we present Immuno-Navigator, a batch-corrected gene expression and coexpression database for 24 cell types of the mouse immune system. We systematically removed batch effects from the underlying gene expression data and showed that this removal considerably improved the consistency between inferred correlations and prior knowledge. The data revealed widespread cell type-specific correlation of expression. Integrated analysis tools allow users to use this correlation of expression for the generation of hypotheses about biological networks and candidate regulators in specific cell types. We show several applications of Immuno-Navigator as examples. In one application we successfully predicted known regulators of importance in naturally occurring Treg cells from their expression correlation with a set of Treg-specific genes. For one high-scoring gene, integrin β8 (Itgb8), we confirmed an association between Itgb8 expression in forkhead box P3 (Foxp3)-positive T cells and Treg-specific epigenetic remodeling. Our results also suggest that the regulation of Tregspecific genes within Treg cells is relatively independent of Foxp3 expression, supporting recent results pointing to a Foxp3-independent component in the development of Treg cells.

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Identification of transcriptional regulators in the mouse immune system

Cited by 181 publications

References 38 publications

Bladder catheterization increases susceptibility to infection that can be prevented by prophylactic antibiotic treatment

Bladder catheterization increases susceptibility to infection that can be prevented by prophylactic antibiotic treatment

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Immuno-Navigator, a batch-corrected coexpression database, reveals cell type-specific gene networks in the immune system

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