O‐GlcNAc cycling and Epigenetics

Abstract

The nutrient‐sensing hexosamine signaling pathway terminating in O‐GlcNAc cycling is emerging as a key epigenetic regulator of gene expression in mammals. Mounting evidence suggests that OGlcNAc cycling sits atop a robust regulatory network maintaining higher‐order chromatin structure and epigenetic memory. OGlcNAc cycling occurs on many cellular targets associated with signaling, morphogenesis and transcriptional regulation. In addition, it has now been added to the multifaceted ‘histone‐code’. In model systems ranging from C. elegans to man, O‐GlcNAc cycling has been shown play an important role in modulating developmental plasticity. We have focused on the influence of O‐GlcNAc cycling upon the molecular modifications of the RNA Polymerase II carboxyl‐terminal tail. In C. elegans, O‐GlcNAc marks the promoters of over 800 developmental, metabolic, and stress‐related genes. In response to starvation or feeding, levels of O‐GlcNAc at promoters remain nearly constant due to dynamic cycling mediated by the transferase OGT‐1 and the O‐GlcNAcase OGA‐1. 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. These studies in the nematode have been extended to the fly and vertebrate RNA Pol II CTD. Our findings suggest a complex interplay between the O‐GlcNAc modification at promoters and the kinase dependent ‘CTD‐code’ regulating RNA Pol II dynamics. Nutrient‐responsive O‐GlcNAc cycling may buffer the transcriptional apparatus from dramatic swings in nutrient availability by sustaining a 5′ pool of RNA Pol II poised for rapid reactivation to meet metabolic and developmental fate decisions. These findings have important implications for the inheritance of susceptibility to the diseases of aging including diabetes, cancer and neurodegeneration.