A Dysregulated DNA Methylation Landscape Linked to Gene Expression in MLL-Rearranged AML
| Autor: | Feifei Zhao, Rakel Tryggvadottir, John Goutsias, Andrew P. Feinberg, Garrett Jenkinson, Ravindra Majeti, Ashley Tetens, Andreas Reinisch, Jordi Abante, Adrian Idrizi, Elisabet Pujadas, Michael A. Koldobskiy |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Bisulfite sequencing Translocation Genetic Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Epigenetic Profile Humans Epigenetics neoplasms Molecular Biology Gene Genetics biology Histone-Lysine N-Methyltransferase Methylation Epigenome DNA Methylation Leukemia Biphenotypic Acute Gene Expression Regulation Neoplastic Leukemia Myeloid Acute 030104 developmental biology KMT2A 030220 oncology & carcinogenesis DNA methylation biology.protein Transcriptome Myeloid-Lymphoid Leukemia Protein Research Paper |
| Zdroj: | Epigenetics |
| ISSN: | 1559-2308 1559-2294 |
| DOI: | 10.1080/15592294.2020.1734149 |
| Popis: | Translocations of the KMT2A (MLL) gene define a biologically distinct and clinically aggressive subtype of acute myeloid leukaemia (AML), marked by a characteristic gene expression profile and few cooperating mutations. Although dysregulation of the epigenetic landscape in this leukaemia is particularly interesting given the low mutation frequency, its comprehensive analysis using whole genome bisulphite sequencing (WGBS) has not been previously performed. Here we investigated epigenetic dysregulation in nine MLL-rearranged (MLL-r) AML samples by comparing them to six normal myeloid controls, using a computational method that encapsulates mean DNA methylation measurements along with analyses of methylation stochasticity. We discovered a dramatically altered epigenetic profile in MLL-r AML, associated with genome-wide hypomethylation and a markedly increased DNA methylation entropy reflecting an increasingly disordered epigenome. Methylation discordance mapped to key genes and regulatory elements that included bivalent promoters and active enhancers. Genes associated with significant changes in methylation stochasticity recapitulated known MLL-r AML expression signatures, suggesting a role for the altered epigenetic landscape in the transcriptional programme initiated by MLL translocations. Accordingly, we established statistically significant associations between discordances in methylation stochasticity and gene expression in MLL-r AML, thus providing a link between the altered epigenetic landscape and the phenotype. |
| Databáze: | OpenAIRE |
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