Epigenetic Effects on Transgene Expression

Gene expression in eukaryotes is regulated primarily at the level of transcription. The genomes of higher eukaryotes contain many more genes than are used in any single differentiated cell type, and cell differentiation can be viewed as the result of decisions regarding which genes will be expressed. The mechanisms of transcriptional control have been intensively studied for more than a decade, resulting in considerable understanding of the organization of DNA elements that control the transcription of individual genes (promoters and enhancers), the factors that bind these elements, and the basal transcription apparatus. These studies have been primarily concerned with mechanisms regulating the rate of transcription of an active gene, rather than mechanisms that determine whether a gene will be transcriptionally active at all. However, it is arguable that the decision to transcribe a gene is the critical determinant; work done over several decades points to complex systems regulating the on/off switch in transcription, but the workings of these systems are still relatively obscure. In general, these systems involve what are termed epigenetic processes, i.e., processes whereby genes are rendered inactive that do not involve changes in the actual DNA sequence. At present there are two known forms of epigenetic modification: DNA methylation and chromatin packaging. Changes in either one or both of these are frequently associated with the silencing of genes.