Class 3 PI3K participates in nuclear gene transcription and co-activates the circadian clock to promote de novo purine synthesis [ChIP-seq]

ABSTRACT: Metabolic demands fluctuate rhythmically and rely on coordination between the circadian clock and nutrient sensing signaling pathways, yet mechanisms of their interaction remain not fully understood. Here, surprisingly, we find that class 3 Phosphatidylinositol-3-kinase (PI3K), known best for its essential role as a lipid kinase in endocytosis and lysosomal degradation by autophagy, has an overlooked nuclear function in participating to gene transcription as a co-activator of heterodimeric transcription factor and circadian driver BMAL1-CLOCK. Canonical pro-catabolic functions of class 3 PI3K in trafficking rely on the indispensable complex between lipid kinase Vps34 and regulatory subunit Vps15. We find that although both subunits of class 3 PI3K interact with RNA Pol2 and co-localize with active transcription sites, exclusive loss of Vps15 blunted BMAL1-CLOCK transcriptional activity. Thus, we established non-redundancy between nuclear Vps34 and Vps15 reflected in a persistent nuclear pool of Vps15 in Vps34-depleted cells and ability of Vps15 to co-activate BMAL1-CLOCK independently of its complex with Vps34. In physiology, we find Vps15 is required for metabolic rhythmicity in liver and, unexpectedly, it promoted pro-anabolic de novo purine nucleotide synthesis. We show Vps15 activated transcription of Ppat, a key enzyme for production of inosine monophosphate, a central metabolic intermediate for purine synthesis. Finally, we demonstrate that in fasting, which represses clock transcriptional activity, BMAL1 recruitment to chromatin is unmodified but it coincides with depletion of Vps15 on the promoters of its targets, Nr1d1 and Ppat. Our findings suggest that nuclear pool of class 3 PI3K Vps15 subunit could couple transcriptional activity of the circadian clock for temporal regulation of energy homeostasis and it opens novel avenues for establishing the complexity for nuclear class 3 PI3K signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE229656 | GEO | 2023/05/09

REPOSITORIES: GEO