O -GlcNAc Integrates the Proteasome and Transcriptome To Regulate Nuclear Hormone Receptors

Abstract

ABSTRACT Mechanisms controlling nuclear hormone receptors are a central question to mammalian developmental and disease processes. Herein, we show that a subtle increase in O -GlcNAc levels inhibits activation of nuclear hormone receptors. In vivo, increased levels of O -GlcNAc impair estrogen receptor activation and cause a decrease in mammary ductal side-branching morphogenesis associated with loss of progesterone receptors. Increased O -GlcNAc levels suppress transcriptional expression of coactivators and of the nuclear hormone receptors themselves. Surprisingly, increased O -GlcNAc levels are also associated with increased transcription of genes encoding corepressor proteins NCoR and SMRT. The association of the enzyme O -GlcNAc transferase with these corepressors contributes to specific regulation of nuclear hormone receptors by O -GlcNAc. Overall, transcriptional inhibition is related to the integrated effect of O -GlcNAc by direct modification of critical elements of the transcriptome and indirectly through O -GlcNAc modification of the proteasome.