Glucose Controls Nuclear Accumulation, Promoter Binding, and Transcriptional Activity of the MondoA-Mlx Heterodimer

Abstract

Maintenance of energy homeostasis is a fundamental requirement for organismal fitness: defective glucose homeostasis underlies numerous metabolic diseases and cancer. At the cellular level, the ability to sense and adapt to changes in intracellular glucose levels is an essential component of this strategy. The basic helix-loop-helix-leucine zipper (bHLHZip) transcription factor complex MondoA-Mlx plays a central role in the transcriptional response to intracellular glucose concentration. MondoA-Mlx complexes accumulate in the nucleus in response to high intracellular glucose concentrations and are required for 75% of glucose-induced transcription. We show here that, rather than simply controlling nuclear accumulation, glucose is required at two additional steps to stimulate the transcription activation function of MondoA-Mlx complexes. Following nuclear accumulation, glucose is required for MondoA-Mlx occupancy at target promoters. Next, glucose stimulates the recruitment of a histone H3 acetyltransferase to promoter-bound MondoA-Mlx to trigger activation of gene expression. Our experiments establish the mechanistic circuitry by which cells sense and respond transcriptionally to various intracellular glucose levels.

We thank Laurie Jackson for technical assistance, Betty Leibold for critical review of the manuscript, the Graves and Cairns labs for reagents and advice, and members of the Ayer lab for helpful discussions and insights.

This work was supported by the Developmental Biology Training Grant T32 HD007491 (C.W.P.), National Institutes of Health grants GM55668 and GM60387 (D.E.A.), and funds from the Huntsman Cancer Foundation. DNA sequencing, oligonucleotide synthesis, and cell imaging facilities were supported by Cancer Center Support grant 2P30 CA42014.