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The role of transposable elements in the regulation of IFN-lambda1 gene expression.

ABSTRACT: IFNs lambda1, lambda2, and lambda3, or type III IFNs, are recently identified cytokines distantly related to type I IFNs. Despite an early evolutionary divergence, the 2 types of IFNs display similar antiviral activities, and both are produced primarily in dendritic cells. Although virus induction of the type I IFN-beta gene had served as a paradigm of gene regulation, relatively little is known about the regulation of IFN-lambda gene expression. Studies of virus induction of IFN-lambda1 identified an essential role of IFN regulatory factors (IRF) 3 and 7, which bind to a regulatory DNA sequence near the start site of transcription. Here, we report that the proximal promoter region of the IFN-lambda1 regulatory region is not sufficient for maximal gene induction in response to bacterial LPS, and we identify an essential cluster of homotypic NF-kappaB binding sites. Remarkably, these sites, which bind efficiently to NF-kappaB and function independently of the IRF3/7 binding sites, originate as transposable elements of the Alu and LTR families. We also show that depletion of the NF-kappaB RelA protein significantly reduces the level of the IFN-lambda1 gene expression. We conclude that IFN-lambda1 gene expression requires NF-kappaB, and we propose a model for IFN-lambda1 gene regulation, in which IRF and NF-kappaB activate gene expression independently via spatially separated promoter elements. These observations provide insights into the independent evolution of the IFN-lambda1 and IFN-beta promoters and directly implicate transposable elements in the regulation of the IFN-lambda1 gene by NF-kappaB.

SUBMITTER: Thomson SJ

PROVIDER: S-EPMC2710658 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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The role of transposable elements in the regulation of IFN-lambda1 gene expression.

Thomson Scott J P SJ Goh Fui G FG Banks Helen H Krausgruber Thomas T Kotenko Sergei V SV Foxwell Brian M J BM Udalova Irina A IA

Proceedings of the National Academy of Sciences of the United States of America 20090701 28

IFNs lambda1, lambda2, and lambda3, or type III IFNs, are recently identified cytokines distantly related to type I IFNs. Despite an early evolutionary divergence, the 2 types of IFNs display similar antiviral activities, and both are produced primarily in dendritic cells. Although virus induction of the type I IFN-beta gene had served as a paradigm of gene regulation, relatively little is known about the regulation of IFN-lambda gene expression. Studies of virus induction of IFN-lambda1 identif ...[more]

PMID: 19570999

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Project description:BackgroundTransposable elements (TEs) are primarily responsible for the DNA losses and gains in genome sequences that occur over time within and between species. TEs themselves evolve, with clade specific LTR/ERV, LINEs and SINEs responsible for the bulk of species-specific genomic features. Because TEs can contain regulatory motifs, they can be exapted as regulators of gene expression. While TE insertions can provide evolutionary novelty for the regulation of gene expression, their overall impact on the evolution of gene expression is unclear. Previous investigators have shown that tissue specific gene expression in amniotes is more similar across species than within species, supporting the existence of conserved developmental gene regulation. In order to understand how species-specific TE insertions might affect the evolution/conservation of gene expression, we have looked at the association of gene expression in six tissues with TE insertions in six representative amniote genomes.ResultsA novel bootstrapping approach has been used to minimise the conflation of effects of repeat types on gene expression. We compared the expression of orthologs containing recent TE insertions to orthologs that contained older TE insertions, and the expression of non-orthologs containing recent TE insertions to non-orthologs with older TE insertions. Both orthologs and non-orthologs showed significant differences in gene expression associated with TE insertions. TEs were found associated with species-specific changes in gene expression, and the magnitude and direction of expression changes were noteworthy. Overall, orthologs containing species-specific TEs were associated with lower gene expression, while in non-orthologs, non-species specific TEs were associated with higher gene expression. Exceptions were SINE elements in human and chicken, which had an opposite association with gene expression compared to other species.ConclusionsOur observed species-specific associations of TEs with gene expression support a role for TEs in speciation/response to selection by species. TEs do not exhibit consistent associations with gene expression and observed associations can vary depending on the age of TE insertions. Based on these observations, it would be prudent to refrain from extrapolating these and previously reported associations to distantly related species.

Project description:IntroductionRecent studies in wheat emphasized the importance of TEs, which occupy ~85% of the wheat genome, as a major source of intraspecific genetic variation due to their recent activity and involvement in genomic rearrangements. The contribution of TEs to structural and functional variations in bread wheat genes is not fully understood.MethodsHere, publicly available RNA-Seq databases of bread wheat were integrated to identify TE insertions within gene bodies (exons\ introns) and assess the impact of TE insertions on gene expression variations of homoeologs gene groups. Overall, 70,818 homoeologs genes were analyzed: 55,170 genes appeared in each one of the three subgenomes (termed ABD), named triads; 12,640 genes appeared in two of the three subgenomes (in A and B only, termed AB; or in A and D only, termed AD; or in B and D only, termed BD);, named dyads; and 3,008 genes underwent duplication in one of the three subgenomes (two copies in: subgenome A, termed AABD; subgenome B, termed ABBD; or subgenome D, termed ABDD), named tetrads.ResultsTo this end, we found that ~36% of the 70,818 genes contained at least one TE insertion within the gene body, mostly in triads. Analysis of 14,258 triads revealed that the presence of TE insertion in at least one of the triad genes (7,439 triads) was associated with balanced expression (similar expression levels) between the homoeolog genes. TE insertions within the exon or in the untranslated regions (UTRs) of one or more of the homoeologs in a triad were significantly associated with homoeolog expression bias. Furthermore, we found a statistically significant correlation between the presence\absence of TEs insertions belonging to six TE superfamilies and 17 TE subfamilies and the suppression of a single homoeolog gene. A significant association was observed between the presence of TE insertions from specific superfamilies and the expression of genes that are associated with biotic and abiotic stress responses.ConclusionOur data strongly indicate that TEs might play a prominent role in controlling gene expression in a genome-specific manner in bread wheat.

Dataset Information

The role of transposable elements in the regulation of IFN-lambda1 gene expression.

Publications

The role of transposable elements in the regulation of IFN-lambda1 gene expression.

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