%A Konzman,Daniel %A Abramowitz,Lara K. %A Steenackers,Agata %A Mukherjee,Mana Mohan %A Na,Hyun-Jin %A Hanover,John A. %D 2020 %J Frontiers in Genetics %C %F %G English %K O-linked β-D-N-acetylglucosamine (O-GlcNAc),X-linked intellectual disability (XLID),epigenetics,histone modification,DNA Methylation,Nutrient-sensing %Q %R 10.3389/fgene.2020.605263 %W %L %M %P %7 %8 2020-November-23 %9 Review %# %! Epigeneitc modifier O-GlcNAc in XLID %* %< %T O-GlcNAc: Regulator of Signaling and Epigenetics Linked to X-linked Intellectual Disability %U https://www.frontiersin.org/articles/10.3389/fgene.2020.605263 %V 11 %0 JOURNAL ARTICLE %@ 1664-8021 %X 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.