O-GlcNAc: Regulator of Signaling and Epigenetics Linked to X-linked Intellectual Disability
Daniel Konzman, Lara K. Abramowitz, Agata Steenackers, M. Mukherjee, Hyun‐Jin Na, John A. Hanover
Abstract
Cellular identity in multicellular organisms is maintained by characteristic transcriptional networks, nutrient consumption, energy production and metabolite utilization. Integrating these cell-specific programs are epigenetic modifiers, whose activity is often dependent on nutrients and their metabolites to function as substrates and co - factors. Emerging data has highlighted the role of the nutrient-sensing enzyme O- GlcNAc transferase (OGT) as an epigenetic modifier essential in coordinating cellular transcriptional programs and metabolic homeostasis. OGT utilizes the end-product of the hexosamine biosynthetic pathway to modify proteins with O- linked β- D - N -acetylglucosamine ( O- GlcNAc). The levels of the modification are held in check by the O- GlcNAcase (OGA). Studies from model organisms and human disease underscore the conserved function these two enzymes of O- GlcNAc cycling play in transcriptional regulation, cellular plasticity and mitochondrial reprogramming. Here, we review these findings and present an integrated view of how O- GlcNAc cycling may contribute to cellular memory and transgenerational inheritance of responses to parental stress. We focus on a rare human genetic disorder where mutant forms of OGT are inherited or acquired de novo . Ongoing analysis of this disorder, OGT- X-linked intellectual disability (OGT-XLID), provides a window into how epigenetic factors linked to O- GlcNAc cycling may influence neurodevelopment.