Limits...
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.

Show MeSH

Related in: MedlinePlus

The transcription factor Ahr is located within the trans-eQTL region for Cyp1a1. The strongest eQTL for Cyp1a1 maps to Chromosome 12 and the QTL peaks between 36 and 37 megabases. The gene Ahr, indicated by an arrow, is located exactly at the top of the QTL peak.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3105947&req=5

Figure 8: The transcription factor Ahr is located within the trans-eQTL region for Cyp1a1. The strongest eQTL for Cyp1a1 maps to Chromosome 12 and the QTL peaks between 36 and 37 megabases. The gene Ahr, indicated by an arrow, is located exactly at the top of the QTL peak.

Mentions: We then performed a search for eQTLs on a global level, for all probe sets. In this analysis 5,214 cis- and 15,485 trans-regulated genes were identified at an LRS threshold of 12 (Table 6 and Figure 6). When the LRS threshold was increased to 50, 1,332 cis-regulated genes were found, whereas the number of trans-regulated genes was reduced to 15. This observation indicates that many of the trans-eQTL showed a much lower significance value than the cis-eQTL. Next, we present examples for one cis- and one trans-eQTL. A strong eQTL was detected on chromosome 14, at 52 megabases (Mb; Figure 7B) regulating the expression levels of Ang (angiogenin, ribonuclease, RNase A family, 5) (Figure 7A). Since Ang is located at the same position as the eQTL (51.7 Mb on chromosome 14) it represents a cis-eQTL. Furthermore, a strong eQTL was found on chromosome 12 regulating the expression levels of the Cyp1a1 gene (cytochrome P450, family 1, subfamily a, polypeptide 1) (Figure 7C,D). Cyp1a1 is located on chromosome 9 and the corresponding eQTL was found on chromosome 12 (trans-eQTL). The eQTL significance interval contained nine genes, four of which were expressed in lung at a level above 10. Ahr (aryl-hydrocarbon receptor) was one of the four genes and was at the top of the QTL peak (Figure 8). It is the most likely candidate for Cyp1a1 regulation. In conclusion, our data set contained a large number of genes whose expression levels are likely to be influenced by allelic variations in the genomes of C57BL/6J and DBA/2J. Therefore, the presence of pairs of regulated genes and their corresponding eQTLs predicts possible regulatory interactions and will allow searching for yet unknown regulatory networks.


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)

The transcription factor Ahr is located within the trans-eQTL region for Cyp1a1. The strongest eQTL for Cyp1a1 maps to Chromosome 12 and the QTL peaks between 36 and 37 megabases. The gene Ahr, indicated by an arrow, is located exactly at the top of the QTL peak.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: The transcription factor Ahr is located within the trans-eQTL region for Cyp1a1. The strongest eQTL for Cyp1a1 maps to Chromosome 12 and the QTL peaks between 36 and 37 megabases. The gene Ahr, indicated by an arrow, is located exactly at the top of the QTL peak.
Mentions: We then performed a search for eQTLs on a global level, for all probe sets. In this analysis 5,214 cis- and 15,485 trans-regulated genes were identified at an LRS threshold of 12 (Table 6 and Figure 6). When the LRS threshold was increased to 50, 1,332 cis-regulated genes were found, whereas the number of trans-regulated genes was reduced to 15. This observation indicates that many of the trans-eQTL showed a much lower significance value than the cis-eQTL. Next, we present examples for one cis- and one trans-eQTL. A strong eQTL was detected on chromosome 14, at 52 megabases (Mb; Figure 7B) regulating the expression levels of Ang (angiogenin, ribonuclease, RNase A family, 5) (Figure 7A). Since Ang is located at the same position as the eQTL (51.7 Mb on chromosome 14) it represents a cis-eQTL. Furthermore, a strong eQTL was found on chromosome 12 regulating the expression levels of the Cyp1a1 gene (cytochrome P450, family 1, subfamily a, polypeptide 1) (Figure 7C,D). Cyp1a1 is located on chromosome 9 and the corresponding eQTL was found on chromosome 12 (trans-eQTL). The eQTL significance interval contained nine genes, four of which were expressed in lung at a level above 10. Ahr (aryl-hydrocarbon receptor) was one of the four genes and was at the top of the QTL peak (Figure 8). It is the most likely candidate for Cyp1a1 regulation. In conclusion, our data set contained a large number of genes whose expression levels are likely to be influenced by allelic variations in the genomes of C57BL/6J and DBA/2J. Therefore, the presence of pairs of regulated genes and their corresponding eQTLs predicts possible regulatory interactions and will allow searching for yet unknown regulatory networks.

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