Glucose controls nuclear accumulation, promoter binding, and transcriptional activity of the MondoA-Mlx heterodimer.
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.
Peterson
Christopher W
CW
Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112-5550, USA.
Stoltzman
Carrie A
CA
Sighinolfi
Michael P
MP
Han
Kyoung-Sim
KS
Ayer
Donald E
DE
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D017124:Conserved Sequence; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D006657:Histones; C550079:MondoA protein, mouse; C501970:Tcfl4 protein, mouse; C445672:Txnip protein, mouse; D013879:Thioredoxins; D051548:Histone Acetyltransferases; D005947:Glucose
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