The following article requires a subscription:



(Format: HTML, PDF)

Glucose regulates programs of gene expression that orchestrate changes in cellular phenotype in several metabolically active tissues. Carbohydrate response element-binding protein (ChREBP) and its binding partner, Mlx, mediate glucose-regulated gene expression by binding to carbohydrate response elements on target genes, such as the prototypical glucose-responsive gene, liver-type pyruvate kinase (Pklr). c-Myc is also required for the glucose response of the Pklr gene, although the relationship between c-Myc and ChREBP has not been defined. Here we describe the molecular events of the glucose-mediated activation of Pklr and determine the effects of decreasing the activity or abundance of c-Myc on this process. Time-course chromatin immunoprecipitation revealed a set of transcription factors [hepatocyte nuclear factor (HNF)1[alpha], HNF4[alpha], and RNA polymerase II (Pol II)] constitutively resident on the Pklr promoter, with a relative enrichment of acetylated histones 3 and 4 in the same region of the gene. Glucose did not affect HNF1[alpha] binding or the acetylation of histones H3 or H4. By contrast, glucose promoted the recruitment of ChREBP and c-Myc and increased the occupancy of HNF4[alpha] and RNA Pol II, which were coincident with the glucose-mediated increase in transcription as determined by a nuclear run-on assay. Depletion of c-Myc activity using a small molecule inhibitor (10058-F4/1RH) abolished the glucose-mediated recruitment of HNF4[alpha], ChREBP, and RNA Pol II, without affecting basal gene expression, histone acetylation, and HNF1[alpha] or basal HNF4[alpha] occupancy. The activation and recruitment of ChREBP to several glucose-responsive genes were blocked by 1RH, indicating a general necessity for c-Myc in this process.

Copyright (C) 2010 by The Endocrine Society