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Global Analysis of the Impact of Environmental Perturbation on cis-Regulation of Gene Expression
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2011 (English)In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 1, e1001279- p.Article in journal (Refereed) Published
Abstract [en]

Genetic variants altering cis-regulation of normal gene expression (cis-eQTLs) have been extensively mapped in human cells and tissues, but the extent by which controlled, environmental perturbation influences cis-eQTLs is unclear. We carried out large-scale induction experiments using primary human bone cells derived from unrelated donors of Swedish origin treated with 18 different stimuli (7 treatments and 2 controls, each assessed at 2 time points). The treatments with the largest impact on the transcriptome, verified on two independent expression arrays, included BMP-2 (t = 2h), dexamethasone (DEX) (t = 24h), and PGE(2) (t = 24h). Using these treatments and control, we performed expression profiling for 18,144 RefSeq transcripts on biological replicates of the complete study cohort of 113 individuals (n(total) = 782) and combined it with genome-wide SNP-genotyping data in order to map treatment-specific cis-eQTLs (defined as SNPs located within the gene +/- 250 kb). We found that 93% of cis-eQTLs at 1% FDR were observed in at least one additional treatment, and in fact, on average, only 1.4% of the cis-eQTLs were considered as treatment-specific at high confidence. The relative invariability of cis-regulation following perturbation was reiterated independently by genome-wide allelic expression tests where only a small proportion of variance could be attributed to treatment. Treatment-specific cis-regulatory effects were, however, 2- to 6-fold more abundant among differently expressed genes upon treatment. We further followed-up and validated the DEX-specific cis-regulation of the MYO6 and TNC loci and found top cis-regulatory variants located 180 kb and 250 kb upstream of the transcription start sites, respectively. Our results suggest that, as opposed to tissue-specificity of cis-eQTLs, the interactions between cellular environment and cis-variants are relatively rare (similar to 1.5%), but that detection of such specific interactions can be achieved by a combination of functional genomic approaches as described here.

Place, publisher, year, edition, pages
2011. Vol. 7, no 1, e1001279- p.
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Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-147767DOI: 10.1371/journal.pgen.1001279ISI: 000286653500018PubMedID: 21283786OAI: oai:DiVA.org:uu-147767DiVA: diva2:401004
Available from: 2011-03-01 Created: 2011-02-28 Last updated: 2015-02-19Bibliographically approved

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Mallmin, HansNilsson, Olle

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