Crosstalk between NUAK1 and the SETD1A complex regulates glycolysis and gluconeogenesis upon glucose deprivation.

Glucose is a crucial energy source, and glucose metabolism represents central chemical reactions in redox homeostasis. We previously found that histone H3 threonine 11 phosphorylation (H3pT11), which requires histone H3 lysine 4 trimethylation (H3K4me3), promotes the transcription of genes regulating mitochondrial respiratory pathways during limited glucose in yeast. Here, we discovered that global levels of H3pT11 increase during glucose depletion in human cells. The human NUAK1 kinase phosphorylates H3T11 and promotes expression of the genes regulating the p53-dependent DNA damage response upon glucose depletion. Remarkably, NUAK1 associates with the SETD1A histone H3K4 methyltransferase complex. Upon glucose depletion NUAK1 and the SETD1A complex promote expression of HK2 and PCK2, which catalyze the first rate-limiting steps of glycolysis and gluconeogenesis, respectively, in addition to genes regulating the mitochondrial respiratory pathway. In combination with constantH3K4me3 levels during glucose depletion, NUAK1 mediated H3T11 phosphorylation may function as the anchor in the rewiring of gene expression during glucose depletion.