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Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures.

Alberts R, Lu L, Williams RW, Schughart K - Respir. Res. (2011)

Bottom Line: Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics.This interval contains the transcription factor Ahr that has a critical mis-sense allele in the DBA/2J haplotype and evidently modulates transcriptional activation by AhR.Large-scale gene expression analyses in genetic reference populations revealed lung-specific and immune-cell gene expression profiles and suggested specific gene regulatory interactions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Infection Genetics, University of Veterinary Medicine Hannover, Inhoffenstr, Braunschweig, Germany.

ABSTRACT

Background: The lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics.

Methods: Steady-state polyA+ mRNA levels were assayed across a diverse and fully genotyped panel of 57 isogenic strains using the Affymetrix M430 2.0 array. Correlations of expression levels between genes were determined. Global expression QTL (eQTL) analysis and network covariance analysis was performed using tools and resources in GeneNetwork http://www.genenetwork.org.

Results: Expression values were highly variable across strains and in many cases exhibited a high heritability factor. Several genes which showed a restricted expression to lung tissue were identified. Using correlations between gene expression values across all strains, we defined and extended memberships of several important molecular networks in the lung. Furthermore, we were able to extract signatures of immune cell subpopulations and characterize co-variation and shared genetic modulation. Known QTL regions for respiratory infection susceptibility were investigated and several cis-eQTL genes were identified. Numerous cis- and trans-regulated transcripts and chromosomal intervals with strong regulatory activity were mapped. The Cyp1a1 P450 transcript had a strong trans-acting eQTL (LOD 11.8) on Chr 12 at 36 ± 1 Mb. This interval contains the transcription factor Ahr that has a critical mis-sense allele in the DBA/2J haplotype and evidently modulates transcriptional activation by AhR.

Conclusions: Large-scale gene expression analyses in genetic reference populations revealed lung-specific and immune-cell gene expression profiles and suggested specific gene regulatory interactions.

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Tissue distribution in 25 other tissues of some of the most highly expressed genes in the lung. The expression levels for (A) Stpc, (B) Ager, (C) Scgb1a1 and (D) Hba-a1 in different tissues are shown. Please note that in this representation the gene is correlated with itself to illustrate only its issue distribution.
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Figure 1: Tissue distribution in 25 other tissues of some of the most highly expressed genes in the lung. The expression levels for (A) Stpc, (B) Ager, (C) Scgb1a1 and (D) Hba-a1 in different tissues are shown. Please note that in this representation the gene is correlated with itself to illustrate only its issue distribution.

Mentions: The large dataset in GeneNetwork and its built-in features allowed us to compare the gene ex-pression patterns in the lung with data from 25 other tissues. First, we identified the most highly expressed genes in lung (Table 2 lists the 15 highest expression signals). Two of these genes were highly restricted to the lung and trachea: Sftpc (surfactant associated protein C) and Ager (advanced glycosylation end product-specific receptor) (Figure 1A, B) whereas Scgb1a1 (secretoglobin, family 1A, member 1 (uteroglobin)) was highly expressed in lung but also showed expression in some other tissues (Figure 1C). On the other hand, Hba-a1 (hemoglobin alpha, adult chain 1) was expressed at high levels in most tissues (Figure 1D). We then used Stfpc in a tissue correlation analysis to identify other genes that may not be as highly expressed but still be restricted to lung tissue. The first 70 probe sets found were then analyzed as above for lung-specific expression, and 15 genes were identified (Table 3). A comparison to the expression patterns described in the BioGPS database [19] confirmed that the majority was only expressed in lung, most of them at high level. Two genes were not restricted to the lung according to BioGPS, and five genes were also found at lower levels in one other tissue (Table 3).


Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures.

Alberts R, Lu L, Williams RW, Schughart K - Respir. Res. (2011)

Tissue distribution in 25 other tissues of some of the most highly expressed genes in the lung. The expression levels for (A) Stpc, (B) Ager, (C) Scgb1a1 and (D) Hba-a1 in different tissues are shown. Please note that in this representation the gene is correlated with itself to illustrate only its issue distribution.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105947&req=5

Figure 1: Tissue distribution in 25 other tissues of some of the most highly expressed genes in the lung. The expression levels for (A) Stpc, (B) Ager, (C) Scgb1a1 and (D) Hba-a1 in different tissues are shown. Please note that in this representation the gene is correlated with itself to illustrate only its issue distribution.
Mentions: The large dataset in GeneNetwork and its built-in features allowed us to compare the gene ex-pression patterns in the lung with data from 25 other tissues. First, we identified the most highly expressed genes in lung (Table 2 lists the 15 highest expression signals). Two of these genes were highly restricted to the lung and trachea: Sftpc (surfactant associated protein C) and Ager (advanced glycosylation end product-specific receptor) (Figure 1A, B) whereas Scgb1a1 (secretoglobin, family 1A, member 1 (uteroglobin)) was highly expressed in lung but also showed expression in some other tissues (Figure 1C). On the other hand, Hba-a1 (hemoglobin alpha, adult chain 1) was expressed at high levels in most tissues (Figure 1D). We then used Stfpc in a tissue correlation analysis to identify other genes that may not be as highly expressed but still be restricted to lung tissue. The first 70 probe sets found were then analyzed as above for lung-specific expression, and 15 genes were identified (Table 3). A comparison to the expression patterns described in the BioGPS database [19] confirmed that the majority was only expressed in lung, most of them at high level. Two genes were not restricted to the lung according to BioGPS, and five genes were also found at lower levels in one other tissue (Table 3).

Bottom Line: Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics.This interval contains the transcription factor Ahr that has a critical mis-sense allele in the DBA/2J haplotype and evidently modulates transcriptional activation by AhR.Large-scale gene expression analyses in genetic reference populations revealed lung-specific and immune-cell gene expression profiles and suggested specific gene regulatory interactions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Infection Genetics, University of Veterinary Medicine Hannover, Inhoffenstr, Braunschweig, Germany.

ABSTRACT

Background: The lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics.

Methods: Steady-state polyA+ mRNA levels were assayed across a diverse and fully genotyped panel of 57 isogenic strains using the Affymetrix M430 2.0 array. Correlations of expression levels between genes were determined. Global expression QTL (eQTL) analysis and network covariance analysis was performed using tools and resources in GeneNetwork http://www.genenetwork.org.

Results: Expression values were highly variable across strains and in many cases exhibited a high heritability factor. Several genes which showed a restricted expression to lung tissue were identified. Using correlations between gene expression values across all strains, we defined and extended memberships of several important molecular networks in the lung. Furthermore, we were able to extract signatures of immune cell subpopulations and characterize co-variation and shared genetic modulation. Known QTL regions for respiratory infection susceptibility were investigated and several cis-eQTL genes were identified. Numerous cis- and trans-regulated transcripts and chromosomal intervals with strong regulatory activity were mapped. The Cyp1a1 P450 transcript had a strong trans-acting eQTL (LOD 11.8) on Chr 12 at 36 ± 1 Mb. This interval contains the transcription factor Ahr that has a critical mis-sense allele in the DBA/2J haplotype and evidently modulates transcriptional activation by AhR.

Conclusions: Large-scale gene expression analyses in genetic reference populations revealed lung-specific and immune-cell gene expression profiles and suggested specific gene regulatory interactions.

Show MeSH
Related in: MedlinePlus