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HDAC inhibitors cause site-specific chromatin remodeling at PU.1-bound enhancers in K562 cells.

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Date
2016
Authors
Frank, Christopher L
Manandhar, Dinesh
Gordân, Raluca
Crawford, Gregory E
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Abstract
BACKGROUND: Small molecule inhibitors of histone deacetylases (HDACi) hold promise as anticancer agents for particular malignancies. However, clinical use is often confounded by toxicity, perhaps due to indiscriminate hyperacetylation of cellular proteins. Therefore, elucidating the mechanisms by which HDACi trigger differentiation, cell cycle arrest, or apoptosis of cancer cells could inform development of more targeted therapies. We used the myelogenous leukemia line K562 as a model of HDACi-induced differentiation to investigate chromatin accessibility (DNase-seq) and expression (RNA-seq) changes associated with this process. RESULTS: We identified several thousand specific regulatory elements [~10 % of total DNase I-hypersensitive (DHS) sites] that become significantly more or less accessible with sodium butyrate or suberanilohydroxamic acid treatment. Most of the differential DHS sites display hallmarks of enhancers, including being enriched for non-promoter regions, associating with nearby gene expression changes, and increasing luciferase reporter expression in K562 cells. Differential DHS sites were enriched for key hematopoietic lineage transcription factor motifs, including SPI1 (PU.1), a known pioneer factor. We found PU.1 increases binding at opened DHS sites with HDACi treatment by ChIP-seq, but PU.1 knockdown by shRNA fails to block the chromatin accessibility and expression changes. A machine-learning approach indicates H3K27me3 initially marks PU.1-bound sites that open with HDACi treatment, suggesting these sites are epigenetically poised. CONCLUSIONS: We find HDACi treatment of K562 cells results in site-specific chromatin remodeling at epigenetically poised regulatory elements. PU.1 shows evidence of a pioneer role in this process by marking poised enhancers but is not required for transcriptional activation.
Type
Journal article
Subject
Acetylation
Chromatin accessibility
Enhancer
Histone deacetylase inhibitor
Pioneer factor
Permalink
https://hdl.handle.net/10161/11948
Published Version (Please cite this version)
10.1186/s13072-016-0065-5
Publication Info
Frank, Christopher L; Manandhar, Dinesh; Gordân, Raluca; & Crawford, Gregory E (2016). HDAC inhibitors cause site-specific chromatin remodeling at PU.1-bound enhancers in K562 cells. Epigenetics Chromatin, 9. pp. 15. 10.1186/s13072-016-0065-5. Retrieved from https://hdl.handle.net/10161/11948.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Crawford

Gregory E. Crawford

Professor in Pediatrics
My research involves identifying gene regulatory elements across the genome to help us understand how chromatin structure dictates cell function and fate. For the last 30 years, mapping chromatin accessible sites has been the gold standard method to identify the location of active regulatory elements, including promoters, enhancers, silencers, and locus control regions. I have developed technologies that can identify most DNase I hypersensitive sites from potentially any cell type from any speci
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