title: Functionally distinct patterns of nucleosome remodeling at enhancers in glucocorticoid-treated acute lymphoblastic leukemia.
abstract: BACKGROUND
  Precise nucleosome positioning is an increasingly recognized feature of promoters and enhancers, reflecting complex contributions of DNA sequence, nucleosome positioning, histone modification and transcription factor binding to enhancer activity and regulation of gene expression. Changes in nucleosome position and occupancy, histone variants and modifications, and chromatin remodeling are also critical elements of dynamic transcriptional regulation, but poorly understood at enhancers. We investigated glucocorticoid receptor-associated (GR) nucleosome dynamics at enhancers in acute lymphoblastic leukemia.
  
  
  RESULTS
  For the first time, we demonstrate functionally distinct modes of nucleosome remodeling upon chromatin binding by GR, which we term central, non-central, phased, and minimal. Central and non-central remodeling reflect nucleosome eviction by GR and cofactors, respectively. Phased remodeling involves nucleosome repositioning and is associated with rapidly activated enhancers and induction of gene expression. Minimal remodeling sites initially have low levels of enhancer-associated histone modification, but the majority of these regions gain H3K4me2 or H3K27Ac to become de novo enhancers. Minimal remodeling regions are associated with gene ontologies specific to decreased B cell number and mTOR inhibition and may make unique contributions to glucocorticoid-induced leukemia cell death.
  
  
  CONCLUSIONS
  Our findings form a novel framework for understanding the dynamic interplay between transcription factor binding, nucleosome remodeling, enhancer function, and gene expression in the leukemia response to glucocorticoids.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA USA.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Wu
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Heath, Boston, MA USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.affiliation: SBH Sciences Inc., Natick, MA USA.
authors.forename: Elinor
authors.initials: E
authors.lastname: Yissachar
authors.affiliation: Morsani College of Medicine, Tampa, FL USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Wischhusen
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Heath, Boston, MA USA.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 281, Memphis, TN 38105 USA.
authors.forename: Charles W M
authors.initials: CWM
authors.lastname: Roberts
keywords: ChIP-seq; Chromatin remodeling; Glucocorticoid receptor; Nucleosome; Transcription enhancer; Transcription regulation