Oncotarget

Research Papers:

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

Magnus Tobiasson _, Hani Abdulkadir, Andreas Lennartsson, Shintaro Katayama, Francesco Marabita, Ayla De Paepe, Mohsen Karimi, Kaarel Krjutskov, Elisabet Einarsdottir, Michael Grövdal, Monika Jansson, Asmaa Ben Azenkoud, Lina Corddedu, Sören Lehmann, Karl Ekwall, Juha Kere, Eva Hellström-Lindberg and Johanna Ungerstedt

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Oncotarget. 2017; 8:28812-28825. https://doi.org/10.18632/oncotarget.15807

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Abstract

Magnus Tobiasson1,*, Hani Abdulkadir1,*, Andreas Lennartsson2, Shintaro Katayama2, Francesco Marabita3,4, Ayla De Paepe1, Mohsen Karimi1, Kaarel Krjutskov2,5,6, Elisabet Einarsdottir2,5, Michael Grövdal1, Monika Jansson1, Asmaa Ben Azenkoud1, Lina Corddedu2, Sören Lehmann1,7, Karl Ekwall2, Juha Kere2,5, Eva Hellström-Lindberg1,* and Johanna Ungerstedt1,*

1Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Division of Hematology Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden

2Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

3Unit of Computational Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

4National Bioinformatics Infrastructure Sweden, Stockholm, Sweden

5Molecular Neurology Research Program, University of Helsinki, and Folkhälsan Institute of Genetics, Helsinki, Finland

6Competence Centre on Health Technologies, Tartu, Estonia

7Department of Medical Sciences, Uppsala University, Uppsala, Sweden

*These authors have contributed equally to this work

Correspondence to:

Magnus Tobiasson, email: johanna.ungerstedt@ki.se

Keywords: MDS, azacitidine, epigenetics, DNA methylation, histone modifications

Received: November 09, 2016    Accepted: February 01, 2017    Published: February 28, 2017

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 β-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.


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