aKG-driven RNA polymerase II transcription of cyclin D1 licenses malic enzyme 2 to promote cell cycle progression

Increased metabolic activity usually provides energy and nutrients for biomass synthesis and is indispensable for the progression of the cell cycle. Here, we found an unexpected role for a-ketoglutarate (aKG) generation in regulating cell cycle gene transcription. A reduction in cellular aKG levels triggered by malic enzyme 2 (ME2) or isocitrate dehydrogenase 1 (IDH1) depletion leads to a pronounced arrest in G1 phase, while aKG supplementation promotes cell cycle progression. Mechanistically, aKG directly binds to RNA polymerase II (RNAPII), increasing the level of RNAPII binding to the cyclin D1 gene promoter, consequently enhancing cyclin D1 transcription. Notably, aKG addition is sufficient to restore cyclin D1 expression in ME2- or IDH1- depleted cells, facilitating cell cycle progression and proliferation in these cells. Therefore, our findings reveal a previously unappreciated function of aKG in gene transcriptional regulation and cell cycle control. Overall design: The sample contains siCtrl, siME2 and siME2+ a KG cells