BHLHE40 role in hepatocytes exposed to high sugar content

In hepatocytes, its function and cooperativity with other TFs are poorly understood. Employing genome-wide approached, we show that its genomic binding strongly overlapped with that of carbohydrate response-element binding protein (ChREBP), a sugar sensing TF and known inducer of BHLHE40 expression.

Transcriptomic analysis of primary mouse hepatocytes revealed a pervasive repressive role for BHLHE40 on genes involved in genomic stability. Bhlhe40 depletion potentiated fructose responsiveness of genes involved in cell cycle regulation. Strikingly, genomic binding of BHLHE40 overlapped with enhancers occupied by PPARα, RXRα, and HNF4 nuclear receptors and BHLHE40 fine-tuned the expression of PPARα target genes.