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SWI/SNF chromatin remodelers act as tumor suppressors in a wide variety of tissue types and cancers. Recent reports describe that as many as 20% of human cancers harbor mutations in one or more subunits of this multi-protein complex. Intriguingly, mutations in the SWI/SNF complex are rarely found in leukemias. However, it has long been understood that SWI/SNF is a key component of glucocorticoid-mediated transcription. Diminished expression of SWI/SNF subunits has also been linked to altered sensitivity to glucocorticoid-induced cell death in acute lymphoblastic leukemias (ALL). Glucocorticoid-induced cell death is a critical component of successful ALL therapy. We therefore use the glucocorticoid-mediated transcriptional program in a human ALL cell line to interrogate the genome-wide chromatin changes and contributions to transcription mediated by an intact SWI/SNF complex. We begin by elucidating the dynamic relationships between glucocorticoid receptor binding to chromatin and recruitment of SWI/SNF using ChIP-Seq. We further relate these glucocorticoid-inducible binding events to changes in position of modified histones, changes in chromatin accessibility by DNase-seq, and changes in gene expression. By better understanding the mechanisms by which SWI/SNF modifies the chromatin landscape within a specific transcriptional program, we will facilitate additional studies of how disruption of the SWI/SNF complex affects ALL responses to steroid therapy. Furthermore, we will contribute to future studies of how mutations in the SWI/SNF complex functionally affect chromatin structure and contribute to oncogenesis. This abstract is also presented as Poster B07. Citation Format: Jennifer Wu, Luca Pinello, Elinor Yissachar, Guo-Cheng Yuan, Charles Roberts. Modulation of chromatin structure and transcription by the SWI/SNF complex in acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR10.

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. Electronic supplementary material The online version of this article (doi:10.1186/s13072-015-0046-0) contains supplementary material, which is available to authorized users.