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Genome-wide analysis of in-trans correlations between copy number and expression with application to human breast cancer

ABSTRACT: Background: Genomic instability is a hallmark of cancer and is frequently reflected in the DNA copy number profile and the expression profile of genes. Methodology is needed to compare array-CGH data and microarray expression data in order to unveil effects of DNA copy number alterations of a gene on the expression of the gene itself (in-cis effects) and on other genes (in-trans effects). Results: We present a method for detection of gene dosage effects on gene expression that first searches for genome-wide in-cis associations between copy number and expression, and then investigates in-trans effects of these genes. A key element of the method is a correction step to eliminate potential confounding effects of in-cis associations when searching for in-trans associations. This facilitates reliable detection of local in-trans associations (i.e. associations within a chromosome) and alleviates the problem of co-occurring copy number aberrations across the genome. Applying the method to data collected from breast carcinomas from 20 women, we found 422 genes with expression levels that are highly correlated to DNA copy number (in-cis) in certain regions of the genome. Of these, 109 (26%) had significant trans-correlation with the expression levels of a large number of genes (20 or more). The strongest trans-regulators were also differentially expressed in subgroups that were found on the basis of expression data by classification of the tumors to previously defined breast cancer subtypes. A study of the most significant in-trans correlated genes yields significant enrichment of certain cancer related pathways and GO terms. Conclusions: We introduce a method for the joint comparative analysis of expression and copy number profiles for the discovery and investigation of in-cis and in-trans regulatory mechanisms. Using data from 20 primary human breast cancers, a number of significant in-trans regulatory genes were found and their biological relevance indicated, calling for the application of the methods on larger data sets. Keywords: Correlations between copy number and gene expression, breast cancer

ORGANISM(S): Homo sapiens

PROVIDER: GSE10583 | GEO | 2010/07/01

SECONDARY ACCESSION(S): PRJNA107849

REPOSITORIES: GEO

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Project description:Gene expression differences between species are driven by both cis and trans effects. Whereas cis effects on gene expression are due to nearby genetic variants, trans effects are due to distal genetic variants that affect diffusible elements such as transcription factors. However, as previous studies have mostly assessed the impacts of cis and trans effects at the gene level, how cis and trans effects differentially impact regulatory elements such as enhancers and promoters remains poorly understood. Here, we used massively parallel reporter assays to directly measure cis and trans effects between human and mouse embryonic stem cells at thousands of individual regulatory elements, including enhancers as well as promoters of both protein-coding and long non-coding RNA genes. Our approach revealed that cis effects are widespread across regulatory elements, and the strongest cis effects are associated with the disruption of motifs recognized by strong transcriptional activators. Conversely, we found that trans effects are rare but stronger in enhancers than promoters, and can be attributed to a subset of transcription factors that are differentially expressed between human and mouse. While previous gene-based studies have found extensive co-occurrence of cis and trans effects in opposite directions that stabilize gene expression between species—or compensatory cis-trans effects—we find that cis-trans compensation is uncommon within individual regulatory elements. Moreover, regulatory elements that do show compensatory cis-trans effects are often less redundant than regulatory elements lacking compensatory cis-trans effects. Thus, our results are consistent with a model wherein compensatory cis-trans effects occur more often through crosstalk between multiple redundant regulatory elements than within a single individual regulatory element. Together, these results indicate that studying the evolution of individual regulatory elements is pivotal to understand the tempo and mode of gene expression evolution.

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Genome-wide analysis of in-trans correlations between copy number and expression with application to human breast cancer

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