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

• Published in: Oncotarget 2017-04, Vol.8 (17), p.28812-28825
• Main Authors: Tobiasson, Magnus, Abdulkadir, Hani, Lennartsson, Andreas, Katayama, Shintaro, Marabita, Francesco, De Paepe, Ayla, Karimi, Mohsen, Krjutskov, Kaarel, Einarsdottir, Elisabet, Grövdal, Michael, Jansson, Monika, Ben Azenkoud, Asmaa, Corddedu, Lina, Lehmann, Sören, Ekwall, Karl, Kere, Juha, Hellström-Lindberg, Eva, Ungerstedt, Johanna
• Format: Article
• Language: English
• Subjects: Antigens, CD34 - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; azacitidine; Azacitidine - pharmacology; Azacitidine - therapeutic use; Bone Marrow Cells - drug effects; Bone Marrow Cells - physiology; Cells, Cultured; Chromatin Immunoprecipitation; Computational Biology; DNA methylation; DNA Methylation - drug effects; Endogenous Retroviruses - genetics; Epigenesis, Genetic; epigenetics; Gene Expression Regulation - drug effects; histone modifications; Histones - metabolism; Humans; MDS; Medicin och hälsovetenskap; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - genetics; Research Paper; Sequence Analysis, RNA; Transcriptome; Treatment Outcome
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.15807

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.