Dynamic O-GIcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity.

Nutrient-driven O-GlcNAcylation of key components of the transcription machinery may epigenetically modulate gene expression in metazoans. The global effects of GlcNAcylation on transcription can be addressed directly in C. elegans because knockouts of the O-GIcNAc cycling enzymes are viable and fertile. Using anti-O-GIcNAc ChIP-on-chip whole-genome tiling arrays on wild-type and mutant strains, we detected over 800 promoters where O-GIcNAc cycling occurs, including microRNA loci and multigene operons. Intriguingly, O-GlcNAc-marked promoters are biased toward genes associated with PIP3 signaling, hexosamine biosynthesis, and lipid/carbohydrate metabolism. These marked genes are linked to insulin-like signaling. metabolism, aging, stress, and pathogen-response pathways in C. elegans. Whole-genome transcriptional profiling of the O- GIcNAc cycling mutants confirmed dramatic deregulation of genes in these key pathways. As predicted, the O-GIcNAc cycling mutants show altered lifespan and UV stress susceptibility phenotypes. We propose that O-GIcNAc cycling at promoters participates in a molecular program impacting nutrient-responsive pathways in C. elegans, including stress, pathogen response, and adult lifespan. The observed impact of O-GIcNAc cycling on both signaling and transcrip- tion in C. elegans has important implications for human diseases of aging, including diabetes and neurodegeneration. [ABSTRACT FROM AUTHOR]

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