Controlling elements are wild cards in the epigenomic deck

The genomes of multicellular eukaryotes are loaded with retrotransposons, parasites that propagate by transcription of their genomes, reverse transcription, and insertion of a new copy into the host genome (1, 2). Waves of replication have formed families of mostly fragmentary or otherwise degenerate retroelements (1, 2). Epigenetic silencing suppresses retrotransposon activity, keeping them from wreaking genetic and epigenetic havoc in their hosts (3, 4), but active suppression must be maintained (2). Discussions of their biological role have focused on genetics: disruption of genomic structure, and adaptation to form regulatory elements and parts of proteins. Less obvious, but possibly far more important, is their ability to disrupt normal patterns of transcription. McClintock observed that DNA transposons in maize could reversibly alter the expression of genes in the general vicinity of their insertion sites, and so termed them “controlling elements” (5). Retrotransposons also have this ability: Depending on their epigenetic state, they may either lie quietly without interfering in affairs or seize control and dramatically change patterns of gene expression. In this issue of PNAS, Kano et al. (6) describe retrotransposon-controlling elements in the murine dactylin gene. Both appear to effect the dactylaplasia phenotype only when epigenetically active, and their activity is regulated by an unlinked modifier. This finding neatly illustrates some properties of controlling elements and promises in time to give new insights into the mechanisms by which they are kept silent (or not). Controlling elements create “transcriptional interference,” in which an inserted or reactivated promoter either alters the activity of a nearby promoter or itself transcribes a gene (7). Importantly, this property is separable from the purely genetic effects of an element's insertion. The variety of their effects tells us something about how little we understand the mechanisms of gene regulation in complex genomes. Because controlling elements …