Nuclear class 3 PI3K co-activates fasting-specific chromatin remodeling

While the regulators of transcription and chromatin organization in fasting are known6-10, how lack of nutrients impacts RNA Pol II (RNAPII) and epigenetic writers remains unclear. Surprisingly, we find that class 3 Phosphatidyl inositol-3 kinase (PI3K-3) lipid kinase, a master regulator of autophagy11, is present at chromatin where it co-activates epigenetic writers for transcriptional activation.

To this end, the chromatin distribution of PI3K-3 largely overlapped with transcriptionally engaged RNAPII phosphorylated on Ser5 (RNAPII-S5p) and Setd1a/COMPASS, the transcription activating H3K4me3 methyltransferase complex12. Mechanistically, nuclear PI3K-3 interacted with RNAPII and the Set1a/COMPASS transcriptional complexes and facilitated their binding. Accordingly, PI3K-3 deletion resulted in lower H3K4me3 and RNAPII-S5p enrichment at selective loci.