Chromatin landscapes of retroviral and transposon integration profiles

PLoS Genet. 2014 Apr 10;10(4):e1004250. doi: 10.1371/journal.pgen.1004250. eCollection 2014 Apr.

Abstract

The ability of retroviruses and transposons to insert their genetic material into host DNA makes them widely used tools in molecular biology, cancer research and gene therapy. However, these systems have biases that may strongly affect research outcomes. To address this issue, we generated very large datasets consisting of ~ 120,000 to ~ 180,000 unselected integrations in the mouse genome for the Sleeping Beauty (SB) and piggyBac (PB) transposons, and the Mouse Mammary Tumor Virus (MMTV). We analyzed ~ 80 (epi)genomic features to generate bias maps at both local and genome-wide scales. MMTV showed a remarkably uniform distribution of integrations across the genome. More distinct preferences were observed for the two transposons, with PB showing remarkable resemblance to bias profiles of the Murine Leukemia Virus. Furthermore, we present a model where target site selection is directed at multiple scales. At a large scale, target site selection is similar across systems, and defined by domain-oriented features, namely expression of proximal genes, proximity to CpG islands and to genic features, chromatin compaction and replication timing. Notable differences between the systems are mainly observed at smaller scales, and are directed by a diverse range of features. To study the effect of these biases on integration sites occupied under selective pressure, we turned to insertional mutagenesis (IM) screens. In IM screens, putative cancer genes are identified by finding frequently targeted genomic regions, or Common Integration Sites (CISs). Within three recently completed IM screens, we identified 7%-33% putative false positive CISs, which are likely not the result of the oncogenic selection process. Moreover, results indicate that PB, compared to SB, is more suited to tag oncogenes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatin / genetics*
  • CpG Islands / genetics
  • DNA Transposable Elements / genetics*
  • Genome / genetics
  • Mice
  • Mutagenesis, Insertional / methods
  • Oncogenes / genetics
  • Retroviridae / genetics*

Substances

  • Chromatin
  • DNA Transposable Elements

Grant support

This work was financed by the Netherlands Consortium for Systems Biology (NCSB) which is part of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research. JdR is supported by the Netherlands Organisation for Scientific Research (NWO-Veni: 639.021.233). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.