Nutrient-Driven O -GlcNAcylation at Promoters Impacts Genome-Wide RNA Pol II Distribution.

Nutrient-driven O -GlcNAcylation has been linked to epigenetic regulation of gene expression in metazoans. In C. elegans, O -GlcNAc marks the promoters of over 800 developmental, metabolic, and stress-related genes; these O -GlcNAc marked genes show a strong 5', promoter-proximal bias in the distribution of RNA Polymerase II (Pol II). In response to starvation or feeding, the steady state distribution of O -GlcNAc at promoters remain nearly constant presumably due to dynamic cycling mediated by the transferase OGT-1 and the O -GlcNAcase OGA-1. However, in viable mutants lacking either of these enzymes of O -GlcNAc metabolism, the nutrient-responsive GlcNAcylation of promoters is dramatically altered. Blocked O -GlcNAc cycling leads to a striking nutrient-dependent accumulation of O -GlcNAc on RNA Pol II. O -GlcNAc cycling mutants also show an exaggerated, nutrient-responsive redistribution of promoter-proximal RNA Pol II isoforms and extensive transcriptional deregulation. Our findings suggest a complex interplay between the O -GlcNAc modification at promoters, the kinase-dependent "CTD-code," and co-factors regulating RNA Pol II dynamics. Nutrient-responsive O -GlcNAc cycling may buffer the transcriptional apparatus from dramatic swings in nutrient availability by modulating promoter activity to meet metabolic and developmental needs.