title: STAT3 acts through pre-existing nucleosome-depleted regions bound by FOS during an epigenetic switch linking inflammation to cancer.
abstract: BACKGROUND
  Transient induction of the Src oncoprotein in a non-transformed breast cell line can initiate an epigenetic switch to a cancer cell via a positive feedback loop that involves activation of the signal transducer and activator of transcription 3 protein (STAT3) and NF-κB transcription factors.
  
  
  RESULTS
  We show that during the transformation process, nucleosome-depleted regions (defined by formaldehyde-assisted isolation of regulatory elements (FAIRE)) are largely unchanged and that both before and during transformation, STAT3 binds almost exclusively to previously open chromatin regions. Roughly, a third of the transformation-inducible genes require STAT3 for the induction. STAT3 and NF-κB appear to drive the regulation of different gene sets during the transformation process. Interestingly, STAT3 directly regulates the expression of NFKB1, which encodes a subunit of NF-κB, and IL6, a cytokine that stimulates STAT3 activity. Lastly, many STAT3 binding sites are also bound by FOS and the expression of several AP-1 factors is altered during transformation in a STAT3-dependent manner, suggesting that STAT3 may cooperate with AP-1 proteins.
  
  
  CONCLUSIONS
  These observations uncover additional complexities to the inflammatory feedback loop that are likely to contribute to the epigenetic switch. In addition, gene expression changes during transformation, whether driven by pre-existing or induced transcription factors, occur largely through pre-existing nucleosome-depleted regions.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Fleming
authors.affiliation: Department of Human Genetics, University of Chicago, 920 E. 58th Street, Chicago, IL 60637 USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Giresi
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Lindahl-Allen
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 USA.
authors.forename: Elsa B
authors.initials: EB
authors.lastname: Krall
authors.affiliation: Department of Human Genetics, University of Chicago, 920 E. 58th Street, Chicago, IL 60637 USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Lieb
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Struhl
keywords: FAIRE; FOS; MCF-10A; STAT3; Transformation