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Global analysis of the impact of environmental perturbation on cis-regulation of gene expression
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نویسنده
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grundberg e. ,adoue v. ,kwan t. ,ge b. ,duan q.l. ,lam k.c.l. ,koka v. ,kindmark a. ,weiss s.t. ,tantisira k. ,mallmin h. ,raby b.a. ,nilsson o. ,pastinen t.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 1
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چکیده
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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 pge2 (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 (ntotal = 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 (~1.5%),but that detection of such specific interactions can be achieved by a combination of functional genomic approaches as described here. © 2011 grundberg et al.
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آدرس
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department of human genetics,mcgill university,montréal,qc,canada,mcgill university and genome québec innovation centre,montréal,qc,canada,the wellcome trust sanger institute,hinxton, United Kingdom, department of human genetics,mcgill university,montréal,qc,canada,mcgill university and genome québec innovation centre,montréal,qc, Canada, department of human genetics,mcgill university,montréal,qc,canada,mcgill university and genome québec innovation centre,montréal,qc, Canada, mcgill university and genome québec innovation centre,montréal,qc, Canada, channing laboratory,department of medicine,brigham and women's hospital,harvard medical school,boston,ma, United States, mcgill university and genome québec innovation centre,montréal,qc, Canada, mcgill university and genome québec innovation centre,montréal,qc, Canada, department of medical sciences,uppsala university,uppsala, Sweden, channing laboratory,department of medicine,brigham and women's hospital,harvard medical school,boston,ma, United States, channing laboratory,department of medicine,brigham and women's hospital,harvard medical school,boston,ma, United States, department of surgical sciences,uppsala university,uppsala, Sweden, channing laboratory,department of medicine,brigham and women's hospital,harvard medical school,boston,ma, United States, department of surgical sciences,uppsala university,uppsala, Sweden, department of human genetics,mcgill university,montréal,qc,canada,mcgill university and genome québec innovation centre,montréal,qc,canada,department of medical genetics,mcgill university,montréal,qc, Canada
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Authors
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