Glucose controls protein-protein interactions and tissue differentiation [ChIP-Seq]

Abstract: Glucose serves as a universal energy currency in living organisms, however, its potential non-energetic biomolecular functions are less well defined. Glucose was among the most increased analytes among >14,000 assessed across epidermal differentiation, an elevation verified in tissue engineered with fluorescent glucose sensors and also observed in differentiating cells from other tissues. Free glucose accumulation, but not its increased metabolism, was essential for epidermal differentiation and required GLUT1, GLUT3, and SLC5A1 transporters. Glucose affinity chromatography and azido-glucose click chemistry revealed direct glucose binding to a variety of regulatory proteins, including the IRF6 transcription factor (TF), whose epidermal knockout confirmed its requirement in glucose-dependent differentiation. Glucose binding mediated IRF6 dimerization, DNA affinity, and genomic targeting. The IRF6R84C mutant found in poorly differentiated cancers was unable to bind glucose. These data demonstrate a non-energetic role for glucose in modulating protein multimerization to control genome dynamics. Purpose: To determine the impact of glucose modulation on IRF6 genomic localization during keratinocyte differentiation