Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease

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Tobiasson , M , Abdulkadir , H , Lennartsson , A , Katayama , S , Marabita , F , De Paepe , A , Karimi , M , Krjutskov , K , Einarsdottir , E , Grovdal , M , Jansson , M , Ben Azenkoud , A , Corddedu , L , Lehmann , S , Ekwall , K , Kere , J , Hellstrom-Lindberg , E & Ungerstedt , J 2017 , ' Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease ' , Oncotarget , vol. 8 , no. 17 , pp. 28812-28825 . https://doi.org/10.18632/oncotarget.15807

Title: Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease
Author: Tobiasson, Magnus; Abdulkadir, Hani; Lennartsson, Andreas; Katayama, Shintaro; Marabita, Francesco; De Paepe, Ayla; Karimi, Mohsen; Krjutskov, Kaarel; Einarsdottir, Elisabet; Grovdal, Michael; Jansson, Monika; Ben Azenkoud, Asmaa; Corddedu, Lina; Lehmann, Soren; Ekwall, Karl; Kere, Juha; Hellstrom-Lindberg, Eva; Ungerstedt, Johanna
Contributor: University of Helsinki, Research Programme for Molecular Neurology
University of Helsinki, Research Programs Unit
University of Helsinki, University of Helsinki
Date: 2017-04-25
Language: eng
Number of pages: 14
Belongs to series: Oncotarget
ISSN: 1949-2553
URI: http://hdl.handle.net/10138/196934
Abstract: Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median beta-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.
Subject: MDS
azacitidine
epigenetics
DNA methylation
histone modifications
ACUTE MYELOID-LEUKEMIA
RISK MYELODYSPLASTIC SYNDROMES
CONVENTIONAL CARE REGIMENS
DECITABINE TREATMENT
OLDER PATIENTS
CANCER CELLS
STEM-CELLS
5-AZACYTIDINE
MUTATIONS
ELEMENTS
3122 Cancers
1182 Biochemistry, cell and molecular biology
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