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Highlights d SRPK1 phosphorylates protamine to initiate paternal genome reprogramming d Phosphorylation site mutations in protamine inhibit protamine-to-histone exchange d Phosphorylated protamine permits efficient recruitment of NPM2 and HIRA d Paternal and maternal genomes undergo synchronized reprogramming upon fertilization

Summary The molecular mechanisms underlying the opposing functions of glucocorticoid receptors (GR) and estrogen receptor α (ERα) in breast cancer development remain poorly understood. Here, we report that in breast cancer cells liganded GR represses a large ERα-activated transcriptional program by binding, in trans, to ERα-occupied enhancers. This abolishes effective activation of these enhancers and their cognate target genes, and leads to inhibition of ERα-dependent binding of components of the MegaTrans complex. Consistent with the effects of SUMOylation on other classes of nuclear receptors, dexamethasone (Dex)-induced trans-repression of the estrogen (E2) program appears to depend on GR SUMOylation, which leads to stable trans-recruitment of the GR-NCoR/SMRT-HDAC3 co-repressor complex on these enhancers. Together, these results uncover a mechanism by which competitive recruitment of DNA-binding nuclear receptors/transcription factors in trans to “hot spot” enhancers serves as an effective biological strategy for trans-repression with clear implications for breast cancer and other diseases.