Abstract
BackgroundPrecise 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.ResultsFor 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0046-0) contains supplementary material, which is available to authorized users.
Highlights
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
glucocorticoid receptor-associated (GR) binding is not restricted to enhancers or DNase I hypersensitivity (DHS) sites We first sought to identify enhancers in the RS4; 11 acute lymphoblastic leukemia cell line, and to characterize GR binding with respect to this existing chromatin landscape
Among GR binding sites, we found that 46 % occur at enhancers having all three marks
Summary
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 occu‐ pancy, histone variants and modifications, and chromatin remodeling are critical elements of dynamic tran‐ scriptional regulation, but poorly understood at enhancers. Gaffney et al have described well-positioned nucleosome arrays flanking transcription factor binding sites within mammalian enhancers [6, 7]. The likelihood that a given segment of DNA is nucleosome-occupied at any given moment is thought to be affected by many factors, including DNA sequence, transcription factor binding, histone modifications and variants, as well as ATP-dependent chromatin remodeling [9, 10]. The number of sequencing reads required by this method remains prohibitively high for experiments aimed at comparisons of nucleosome position and occupancy among multiple conditions or at individual genomic locations
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