AMPK regulates histone H2B O-GlcNAcylation

Abstract

Histone H2B O-GlcNAcylation is an important post-translational modification of chromatin during gene transcription. However, how this epigenetic modification is regulated remains unclear. Here we found that the energy-sensing adenosine-monophosphate-activated protein kinase (AMPK) could suppress histone H2B O-GlcNAcylation. AMPK directly phosphorylates O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT). Although this phosphorylation does not regulate the enzymatic activity of OGT, it inhibits OGT–chromatin association, histone O-GlcNAcylation and gene transcription. Conversely, OGT also O-GlcNAcylates AMPK and positively regulates AMPK activity, creating a feedback loop. Taken together, these results reveal a crosstalk between the LKB1-AMPK and the hexosamine biosynthesis (HBP)-OGT pathways, which coordinate together for the sensing of nutrient state and regulation of gene transcription.

Exploring the emerging complexity in transcriptional regulation of energy homeostasis

“…It is noteworthy that UDP-GlcNAc is the second most abundant nucleotide in the cell after ATP. O-GlcNAcylation of H2B at serine 112 has been associated with active gene transcription during times of positive energy balance 66 . However, the impact of these mechanisms on transcriptional regulation in the context of energy homeostasis remains largely uncharted.…”

“…In a recent study, AMP-activated protein kinase (AMPK) was shown to reduce histone H2B O-GlcNAcylation by phosphorylation of O-GlcNAc transferase (OGT). AMPK is also O-GlcNAcylated itself, creating a regulatory feedback loop between OGT and AMPK 66 . AMPK was also shown to associate directly with chromatin at p53-binding sites, leading to phosphorylation of H2B at serine 36 and regulation of p53-dependent genes such as Cdkn1a (which encodes p21), Cpt1c (carnitine palmitoyltransferase 1C), Rprm (reprimo) and cyclin G 68 .…”

Undetectable histone O-GlcNAcylation in mammalian cells

“…14,15,31,33 Upon further characterization, it was reported that histone H2B S112 O-GlcNAcylation promotes H2B monoubiquitination on lysine 120 (H2B K120ub), an event associated with transcriptional activation. 33,34 On the other hand, histone H3 serine 10 was also reported to be O-GlcNAcylated, and this appears to compete with the phosphorylation of this site as well as modulate the transcriptional state of chromatin. 14,15 Other O-GlcNAcylation sites were reported within the globular domains of histones suggesting that they may function in maintaining higher-order chromatin structure.…”

“…32,35 To further investigate the potential biological significance of histone OGlcNAcylation, we initially sought to reproduce previously published results on the modification of histones H2B and H2A. 14,30,[32][33][34] We co-expressed Flag-H2B or Flag-H2A with either Myc-OGT or the D925A catalytic inactive mutant (Myc-OGT CD). 36 Co-expression of Myc-TET2 with Myc-OGT was also included, since their association was expected to significantly increase OGT-mediated histone OGlcNAcylation.…”

The potential role of O-GlcNAc modification in cancer epigenetics

“…Recent studies have also shown an important role of AMPK in O-GlcNAcylation of H2B. Xu et al found that AMPK can phosphorylate OGT at Thr444 and that this phosphorylation blocks OGT recruitment to chromatin and suppress histone O-GlcNAcylation [23]. However, under high nutrition conditions, the AMPK is inactivated and OGT can bind and modify H2B.…”