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Butyrate mediates decrease of histone acetylation centered on transcription start sites and down-regulation of associated genes
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.ORCID-id: 0000-0001-6085-6749
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2007 (engelsk)Inngår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 17, nr 6, s. 708-719Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Butyrate is a histone deacetylase inhibitor (HDACi) with anti-neoplastic properties, which theoretically reactivates epigenetically silenced genes by increasing global histone acetylation. However, recent studies indicate that a similar number or even more genes are down-regulated than up-regulated by this drug. We treated hepatocarcinoma HepG2 cells with butyrate and characterized the levels of acetylation at DNA-bound histones H3 and H4 by ChIP-chip along the ENCODE regions. In contrast to the global increases of histone acetylation, many genomic regions close to transcription start sites were deacetylated after butyrate exposure. In order to validate these findings, we found that both butyrate and trichostatin A treatment resulted in histone deacetylation at selected regions, while nucleosome loss or changes in histone H3 lysine 4 trimethylation (H3K4me3) did not occur in such locations. Furthermore, similar histone deacetylation events were observed when colon adenocarcinoma HT-29 cells were treated with butyrate. In addition, genes with deacetylated promoters were down-regulated by butyrate, and this was mediated at the transcriptional level by affecting RNA polymerase II (POLR2A) initiation/elongation. Finally, the global increase in acetylated histones was preferentially localized to the nuclear periphery, indicating that it might not be associated to euchromatin. Our results are significant for the evaluation of HDACi as anti-tumourogenic drugs, suggesting that previous models of action might need to be revised, and provides an explanation for the frequently observed repression of many genes during HDACi treatment.

sted, utgiver, år, opplag, sider
2007. Vol. 17, nr 6, s. 708-719
Emneord [en]
Acetylation/drug effects, Adenocarcinoma/*metabolism, Butyrates/*pharmacology, Cell Line; Tumor, Colonic Neoplasms/*metabolism, Enzyme Inhibitors/*pharmacology, Gene Expression Profiling, Gene Expression Regulation; Neoplastic/*drug effects, Histone Deacetylases/antagonists & inhibitors/metabolism, Histones/*metabolism, Humans, Neoplasm Proteins/*metabolism, Oligonucleotide Array Sequence Analysis, Protein Processing; Post-Translational/*drug effects
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Identifikatorer
URN: urn:nbn:se:uu:diva-17397DOI: 10.1101/gr.5540007ISI: 000247226900005PubMedID: 17567991OAI: oai:DiVA.org:uu-17397DiVA, id: diva2:45168
Tilgjengelig fra: 2008-06-23 Laget: 2008-06-23 Sist oppdatert: 2017-12-08bibliografisk kontrollert

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