TY - JOUR T1 - Nutrient sensitive protein <em>O</em>-GlcNAcylation modulates the transcriptome through epigenetic mechanisms during embryonic neurogenesis JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201385 VL - 5 IS - 8 SP - e202201385 AU - Shama Parween AU - Thilina T Alawathugoda AU - Ashok D Prabakaran AU - S Thameem Dheen AU - Randall H Morse AU - Bright Starling Emerald AU - Suraiya A Ansari Y1 - 2022/08/01 UR - https://www.life-science-alliance.org/content/5/8/e202201385.abstract N2 - Protein O-GlcNAcylation is a dynamic, nutrient-sensitive mono-glycosylation deposited on numerous nucleo-cytoplasmic and mitochondrial proteins, including transcription factors, epigenetic regulators, and histones. However, the role of protein O-GlcNAcylation on epigenome regulation in response to nutrient perturbations during development is not well understood. Herein we recapitulated early human embryonic neurogenesis in cell culture and found that pharmacological up-regulation of O-GlcNAc levels during human embryonic stem cells’ neuronal differentiation leads to up-regulation of key neurogenic transcription factor genes. This transcriptional de-repression is associated with reduced H3K27me3 and increased H3K4me3 levels on the promoters of these genes, perturbing promoter bivalency possibly through increased EZH2-Thr311 phosphorylation. Elevated O-GlcNAc levels also lead to increased Pol II-Ser5 phosphorylation and affect H2BS112O-GlcNAc and H2BK120Ub1 on promoters. Using an in vivo rat model of maternal hyperglycemia, we show similarly elevated O-GlcNAc levels and epigenetic dysregulations in the developing embryo brains because of hyperglycemia, whereas pharmacological inhibition of O-GlcNAc transferase (OGT) restored these molecular changes. Together, our results demonstrate O-GlcNAc mediated sensitivity of chromatin to nutrient status, and indicate how metabolic perturbations could affect gene expression during neurodevelopment. ER -