A network of epigenetic modifiers and DNA repair genes controls tissue-specific copy number alteration preference
Abstract
Copy number alterations (CNAs) in cancer patients show a large variability in their number, length and position. CNA number and length are linked to patient survival suggesting clinical relevance. However, the sources of this variability are not known. We have identified genes that tend to be mutated in samples having few or many CNAs, which we term CONIM genes (COpy Number Instability Modulators). CONIM proteins cluster into a densely connected subnetwork of physical interactions and many of them are epigenetic modifiers. Therefore, we investigate how the epigenome of the tissue-of-origin influences the position of CNA breakpoints and the properties of the resulting CNAs. We find that the presence of heterochromatin in the tissue-of-origin contributes to the recurrence and length of CNAs in the respective cancer type.
Data availability
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HIPPIE protein-protein interactionsPublicly available at the Human Integrated Protein-Protein Interaction rEference website.
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Chromatin state model (18 states)Publicly available at NIH Roadmap Epigenomics Mapping Consortium.
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Histone ChIP-seq peaksPublicly available at NIH Roadmap Epigenomics Mapping Consortium.
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RNA expression (RNAseq)Publicly available at NIH Roadmap Epigenomics Mapping Consortium.
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SNP6 focal copy altered segmentsPublicly available at the Broad Institute website.
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Illumina HiSeq copy number dataPublicly available at the Broad Institute website.
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SNP6 recurrent copy number alterations (GISTIC2)Publicly available at the Broad Institute website.
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Mutation dataPublicly available at the Broad Institute website.
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (SCHAÂ 1933/1-1)
- Martin H Schaefer
European Commission (HEALTH-F4-2011-278568)
- Luis Serrano
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Cramer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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Enhancers and promoters are classically considered to be bound by a small set of transcription factors (TFs) in a sequence-specific manner. This assumption has come under increasing skepticism as the datasets of ChIP-seq assays of TFs have expanded. In particular, high-occupancy target (HOT) loci attract hundreds of TFs with often no detectable correlation between ChIP-seq peaks and DNA-binding motif presence. Here, we used a set of 1003 TF ChIP-seq datasets (HepG2, K562, H1) to analyze the patterns of ChIP-seq peak co-occurrence in combination with functional genomics datasets. We identified 43,891 HOT loci forming at the promoter (53%) and enhancer (47%) regions. HOT promoters regulate housekeeping genes, whereas HOT enhancers are involved in tissue-specific process regulation. HOT loci form the foundation of human super-enhancers and evolve under strong negative selection, with some of these loci being located in ultraconserved regions. Sequence-based classification analysis of HOT loci suggested that their formation is driven by the sequence features, and the density of mapped ChIP-seq peaks across TF-bound loci correlates with sequence features and the expression level of flanking genes. Based on the affinities to bind to promoters and enhancers we detected five distinct clusters of TFs that form the core of the HOT loci. We report an abundance of HOT loci in the human genome and a commitment of 51% of all TF ChIP-seq binding events to HOT locus formation thus challenging the classical model of enhancer activity and propose a model of HOT locus formation based on the existence of large transcriptional condensates.