title: Epigenetic coordination of signaling pathways during the epithelial-mesenchymal transition.
abstract: BACKGROUND
  The epithelial-mesenchymal transition (EMT) is a de-differentiation process required for wound healing and development. In tumors of epithelial origin aberrant induction of EMT contributes to cancer progression and metastasis. Studies have begun to implicate epigenetic reprogramming in EMT; however, the relationship between reprogramming and the coordination of cellular processes is largely unexplored. We have previously developed a system to study EMT in a canonical non-small cell lung cancer (NSCLC) model. In this system we have shown that the induction of EMT results in constitutive NF-κB activity. We hypothesized a role for chromatin remodeling in the sustained deregulation of cellular signaling pathways.
  
  
  RESULTS
  We mapped sixteen histone modifications and two variants for epithelial and mesenchymal states. Combinatorial patterns of epigenetic changes were quantified at gene and enhancer loci. We found a distinct chromatin signature among genes in well-established EMT pathways. Strikingly, these genes are only a small minority of those that are differentially expressed. At putative enhancers of genes with the 'EMT-signature' we observed highly coordinated epigenetic activation or repression. Furthermore, enhancers that are activated are bound by a set of transcription factors that is distinct from those that bind repressed enhancers. Upregulated genes with the 'EMT-signature' are upstream regulators of NF-κB, but are also bound by NF-κB at their promoters and enhancers. These results suggest a chromatin-mediated positive feedback as a likely mechanism for sustained NF-κB activation.
  
  
  CONCLUSIONS
  There is highly specific epigenetic regulation at genes and enhancers across several pathways critical to EMT. The sites of these changes in chromatin state implicate several inducible transcription factors with critical roles in EMT (NF-κB, AP-1 and MYC) as targets of this reprogramming. Furthermore, we find evidence that suggests that these transcription factors are in chromatin-mediated transcriptional feedback loops that regulate critical EMT genes. In sum, we establish an important link between chromatin remodeling and shifts in cellular reprogramming.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Cieślik
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hoang
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.
authors.forename: Natalya
authors.initials: N
authors.lastname: Baranova
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Chodaparambil
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Allison
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.
authors.forename: J Jacob
authors.initials: JJ
authors.lastname: Wamsley
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Gray
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.|Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.
authors.forename: Marty W
authors.initials: MW
authors.lastname: Mayo
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, P.O. Box 800733, Charlottesville, VA 22908, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bekiranov