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Oncotarget. 2017 Apr 25;8(17):28812-28825. doi: 10.18632/oncotarget.15807.

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 information

1
Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Division of Hematology Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
2
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm County, Sweden.
3
Unit of Computational Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
4
National Bioinformatics Infrastructure Sweden, Stockholm, Sweden.
5
Molecular Neurology Research Program, University of Helsinki, and Folkhälsan Institute of Genetics, Helsinki, Finland.
6
Competence Centre on Health Technologies, Tartu, Estonia.
7
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

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.

KEYWORDS:

DNA methylation; MDS; azacitidine; epigenetics; histone modifications

PMID:
28427179
PMCID:
PMC5438694
DOI:
10.18632/oncotarget.15807
[Indexed for MEDLINE]
Free PMC Article

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