The enduring mystery of intron-mediated enhancement

Within two years of their discovery in 1977, introns were found to have a positive effect on gene expression. Numerous examples of stimulatory introns have been described since then in very diverse organisms, including plants. In some cases, the mechanism through which the intron affects expression is readily understood. However, many introns that affect expression increase mRNA accumulation through an unknown mechanism, referred to as intron-mediated enhancement (IME). Despite several decades of research into IME, and the clear benefits of using introns to increase transgene expression, little progress has been made in understanding the mechanism of IME. Several fundamental questions regarding the role of transcription and splicing, the sequences responsible for IME, the involvement of other factors, and the relationship between introns and promoters remain unanswered. The more we learn about the properties of stimulating introns, the clearer it becomes that the effects of introns are unfamiliar and difficult to reconcile with conventional views of how transcription is controlled. We hypothesize that introns increase transcript initiation upstream of themselves by creating a localized region of accessible chromatin. Introns might represent a novel kind of downstream regulatory element for genes transcribed by RNA polymerase II.