Transcription factor assisted loading and enhancer dynamics dictate the hepatic fasting response

• Autores: Goldstein, Ido; Baek, Songjoon; Presman, Diego Martin; Paakinaho, Ville; Swinstead, Erin E.; Hager, Gordon L.
• Año de publicación: 2017
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: DYNAMIC ASSISTED LOADING; FASTING; LIVER
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Fasting elicits transcriptional programs in hepatocytes leading to glucose and ketone production. This transcriptional program is regulated by many transcription factors (TFs). To understand how this complex network regulates the metabolic response to fasting, we aimed at isolating the enhancers and TFs dictating it. Measuring chromatin accessibility revealed that fasting massively reorganizes liver chromatin, exposing numerous fasting-induced enhancers. By utilizing computational methods in combination with dissecting enhancer features and TF cistromes, we implicated four key TFs regulating the fasting response: glucocorticoid receptor (GR), cAMP responsive element binding protein 1 (CREB1), peroxisome proliferator activated receptor alpha (PPARA), and CCAAT/enhancer binding protein beta (CEBPB). These TFs regulate fuel production by two distinctly operating modules, each controlling a separate metabolic pathway. The gluconeogenic module operates through assisted loading, whereby GR doubles the number of sites occupied by CREB1 as well as enhances CREB1 binding intensity and increases accessibility of CREB1 binding sites. Importantly, this GR-assisted CREB1 binding was enhancer-selective and did not affect all CREB1-bound enhancers. Single-molecule tracking revealed that GR increases the number and DNA residence time of a portion of chromatin-bound CREB1 molecules. These events collectively result in rapid synergistic gene expression and higher hepatic glucose production. Conversely, the ketogenic module operates via a GR-induced TF cascade, whereby PPARA levels are increased following GR activation, facilitating gradual enhancer maturation next to PPARA target genes and delayed ketogenic gene expression. Our findings reveal a complex network of enhancers and TFs that dynamically cooperate to restore homeostasis upon fasting.
Fil: Goldstein, Ido. National Cancer Institute; Estados Unidos
Fil: Baek, Songjoon. National Cancer Institute; Estados Unidos
Fil: Presman, Diego Martin. National Cancer Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Paakinaho, Ville. National Cancer Institute; Estados Unidos
Fil: Swinstead, Erin E.. National Cancer Institute; Estados Unidos
Fil: Hager, Gordon L.. National Cancer Institute; Estados Unidos