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

Heterochromatin has crucial functions in protecting genome integrity. In mouse cells, heterochromatin is characterized by A/T-rich, 234 bp DNA repeat arrays, called the 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 derepress 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 hrs exposure of mouse embryonic fibroblasts (MEF) to genistein results in a more than 100-fold induction of MSR transcripts. This derepression 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 derepression of MSR transcription. Mechanistically, DNA topoisomerase poisons phenocopy the genistein-dependent desilencing 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. In addition, the data reveal a novel function for genistein in derepressing MSR transcription that may contribute to the growth inhibitory and anticancer properties of this natural compound.