The isoflavone genistein selectively stimulates major satellite repeat transcription in mouse heterochromatin

Mouse heterochromatin is characterized by A/T-rich, 234 bp DNA repeat arrays, called major satellite repeats (MSR). We investigated MSR expression in response to a variety of stress conditions by using small molecule compounds. We identified the isoflavone genistein to selectively stimulate MSR transcription, but not that of other DNA repeat elements. Genistein is a natural compound that is frequently used in dietary supplements and has been associated with reducing cancer risk. A 24 h exposure of mouse embryonic fibroblasts (MEF) to genistein results in a more than 100-fold induction of MSR transcripts. This up-regulation depends on the activity of RNA polymerase II and requires a cycling G1 cell population. Blocking the cell cycle at the G2/M stage significantly attenuates genistein-mediated stimulation of MSR transcription. Mechanistically, DNA topoisomerase poisons phenocopy the genistein-dependent up-regulation of MSR expression. Together, these data suggest that MSR transcriptional response is guided by an altered topology of the underlying A/T-rich MSR DNA repeat arrays and reveal a novel function for genistein that may contribute to the anticancer properties of this natural compound.