title: TNFα signalling primes chromatin for NF-κB binding and induces rapid and widespread nucleosome repositioning.
abstract: BACKGROUND
  The rearrangement of nucleosomes along the DNA fiber profoundly affects gene expression, but little is known about how signalling reshapes the chromatin landscape, in three-dimensional space and over time, to allow establishment of new transcriptional programs.
  
  
  RESULTS
  Using micrococcal nuclease treatment and high-throughput sequencing, we map genome-wide changes in nucleosome positioning in primary human endothelial cells stimulated with tumour necrosis factor alpha (TNFα) - a proinflammatory cytokine that signals through nuclear factor kappa-B (NF-κB). Within 10 min, nucleosomes reposition at regions both proximal and distal to NF-κB binding sites, before the transcription factor quantitatively binds thereon. Similarly, in long TNFα-responsive genes, repositioning precedes transcription by pioneering elongating polymerases and appears to nucleate from intragenic enhancer clusters resembling super-enhancers. By 30 min, widespread repositioning throughout megabase pair-long chromosomal segments, with consequential effects on three-dimensional structure (detected using chromosome conformation capture), is seen.
  
  
  CONCLUSIONS
  Whilst nucleosome repositioning is viewed as a local phenomenon, our results point to effects occurring over multiple scales. Here, we present data in support of a TNFα-induced priming mechanism, mostly independent of NF-κB binding and/or elongating RNA polymerases, leading to a plastic network of interactions that affects DNA accessibility over large domains.
authors.forename: Sarah
authors.initials: S
authors.lastname: Diermeier
authors.forename: Petros
authors.initials: P
authors.lastname: Kolovos
authors.forename: Leonhard
authors.initials: L
authors.lastname: Heizinger
authors.forename: Uwe
authors.initials: U
authors.lastname: Schwartz
authors.forename: Theodore
authors.initials: T
authors.lastname: Georgomanolis
authors.forename: Anne
authors.initials: A
authors.lastname: Zirkel
authors.forename: Gero
authors.initials: G
authors.lastname: Wedemann
authors.forename: Frank
authors.initials: F
authors.lastname: Grosveld
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Knoch
authors.forename: Rainer
authors.initials: R
authors.lastname: Merkl
authors.forename: Peter R
authors.initials: PR
authors.lastname: Cook
authors.forename: Gernot
authors.initials: G
authors.lastname: Längst
authors.forename: Argyris
authors.initials: A
authors.lastname: Papantonis
mesh_terms: D001665:Binding Sites; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008969:Molecular Sequence Data; D052002:NF-kappa B p50 Subunit / Q000737:chemistry / Q000378:metabolism*; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D009707:Nucleosomes; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D012321:DNA-Directed RNA Polymerases