The impact of foreign DNA integration on tumor biology and evolution via epigenetic alterations

Abstract

The insertion of foreign DNA into established mammalian genomes leads to the de novo methylation and frequently to the silencing of the transgenome. Moreover, foreign DNA integration causes epigenetic and functional changes extending to sites in the genome remote from the point of foreign DNA insertion. DNA methylation and transcription patterns can become globally altered in the recipient genomes. In viral and perhaps in general oncogenesis, the fundamental alterations of cellular transcriptional profiles are thought to be due to these epigenetic effects. The contributions of oncogenes and tumor suppressor genes during oncogenic transformation may be only part of a much more generalized transcriptional reprogramming upon integration of foreign DNA. Retrotransposon and ancient retroviral insertions may have enacted evolutionary mechanisms via epigenetic changes and subsequent selection. In this context, essential effects of the integration of large numbers of retroviral and retrotransposon sequences into ancestral genomes are seen in their potential of having altered the epigenetic repertoire of the recipient genome at the time of impact. Each insertion event had in its wake an altered epigenome of the host cell which was then selected for or against under the conditions prevalent at the time of retrotransposon or retroviral insertions. This novel model ascribes a significant evolutionary effect not merely to the addition of genetically stable retrotransposon information but rather to its epigenetic consequences.