O-GlcNAc: Regulator of Signaling and Epigenetics Linked to X-linked Intellectual Disability.

Daniel Konzman,Agata Steenackers,Hyun-Jin Na,John A Hanover,Lara K Abramowitz,Mana Mohan Mukherjee

doi:10.3389/fgene.2020.605263

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.

Highlights

Throughout the lifetime of an organism there is a requirement to be able to adapt to environmental changes, whether that be development, stress, or nutritional state
We focus on the conserved epigenetic role that the nutrient-sensitive post-translational modification (PTM) O-GlcNAc, and the enzymes involved in O-GlcNAc cycling, the O-GlcNAc transferase (OGT) and the O-GlcNAcase (MGEA5 or OGA) have in coordinating transcriptional responses to environmental changes
We demonstrate that O-GlcNAc participates in an autoregulatory feedback loop where CHK1/CHK2 stabilizes OGT, allowing further O-GlcNAcylation that continues to activate the DNA damage response (DDR) pathway (Na et al, 2020) (Figure 2)

Summary

Introduction

Throughout the lifetime of an organism there is a requirement to be able to adapt to environmental changes, whether that be development, stress, or nutritional state. In addition to the necessary role of O-GlcNAc in the Polycomb repressive complex, this modification is involved in transcriptional activation, highlighting the diverse routes in which O-GlcNAc regulates gene expression.

Results

Conclusion