title: Integrative genomic analysis of CREB defines a critical role for transcription factor networks in mediating the fed/fasted switch in liver.
abstract: BACKGROUND
  Metabolic homeostasis in mammals critically depends on the regulation of fasting-induced genes by CREB in the liver. Previous genome-wide analysis has shown that only a small percentage of CREB target genes are induced in response to fasting-associated signaling pathways. The precise molecular mechanisms by which CREB specifically targets these genes in response to alternating hormonal cues remain to be elucidated.
  
  
  RESULTS
  We performed chromatin immunoprecipitation coupled to high-throughput sequencing of CREB in livers from both fasted and re-fed mice. In order to quantitatively compare the extent of CREB-DNA interactions genome-wide between these two physiological conditions we developed a novel, robust analysis method, termed the 'single sample independence' (SSI) test that greatly reduced the number of false-positive peaks. We found that CREB remains constitutively bound to its target genes in the liver regardless of the metabolic state. Integration of the CREB cistrome with expression microarrays of fasted and re-fed mouse livers and ChIP-seq data for additional transcription factors revealed that the gene expression switches between the two metabolic states are associated with co-localization of additional transcription factors at CREB sites.
  
  
  CONCLUSIONS
  Our results support a model in which CREB is constitutively bound to thousands of target genes, and combinatorial interactions between DNA-binding factors are necessary to achieve the specific transcriptional response of the liver to fasting. Furthermore, our genome-wide analysis identifies thousands of novel CREB target genes in liver, and suggests a previously unknown role for CREB in regulating ER stress genes in response to nutrient influx.
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Logan J
authors.initials: LJ
authors.lastname: Everett
authors.forename: John
authors.initials: J
authors.lastname: Le Lay
authors.forename: Sabina
authors.initials: S
authors.lastname: Lukovac
authors.forename: Diana
authors.initials: D
authors.lastname: Bernstein
authors.forename: David J
authors.initials: DJ
authors.lastname: Steger
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
mesh_terms: D000818:Animals; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004435:Eating; D005215:Fasting / Q000378:metabolism*; D005786:Gene Expression Regulation; D023281:Genomics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004247:DNA