HDAC inhibitors cause site-specific chromatin remodeling at PU.1-bound enhancers in K562 cells.
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.
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https://hdl.handle.net/10161/11948Published Version (Please cite this version)
10.1186/s13072-016-0065-5Publication 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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Show full item recordScholars@Duke
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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