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. To investigate the effect of genistein on regulating transcription of MSR repeats. Wile-type, control and MEFs treated with 50uM genistein for 24hours were used for this experiment.