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Epigenomic re-confi...
Epigenomic re-configuration of primary multiple myeloma underlies the synergistic effect of combined DNMT and EZH2 inhibition.
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Atienza-Párraga, Alba (author)
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Diamanti, Klev (author)
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Nylund, Patrick (author)
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Skaftason, Aron (author)
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Ma, Anqi (author)
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Jin, Jian (author)
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Martín-Subero, José Ignacio (author)
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Öberg, Fredrik (author)
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Komorowski, Jan (author)
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Jernberg-Wiklund, Helena (author)
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Kalushkova, Antonia (author)
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- English.
- Related links:
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https://urn.kb.se/re...
Abstract
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- Multiple myeloma (MM) is characterized by an overexpression of EZH2 and a subsequent increase in H3K27me3-mediated silencing. However, the genome-wide redistribution of this mark in context with other epigenetic tags remains largely unexplored. Here, we show that EZH2 physically interacts with DNMT1 and that combined inhibition leads to a reduced G2/M arrest and increased apoptosis in MM. In addition, we present a catalogue of the genomic regulatory regions in normal plasma cells (NPC) as defined by their individual combination of histone marks. We used ChIP-seq and ATAC-seq data to generate whole-genome NPC chromatin annotations which we further analysed using DNA methylation arrays and RNA-seq. Comparison between NPC and MM demonstrated that, despite the global hypomethylation, enhancers show a tendency towards a higher DNA methylation levels in MM, whereas Polycomb and heterochromatic sites, highly methylated in NPC, show intermediate levels of the mark. Across all examined regulatory regions, 5-azacytidine treatment strongly reduced DNA methylation in MM. Furthermore, we find an extensive re-structuration of the global histone patterns in MM. We noticed a widespread increase in H3K27me3 except at active TSSs/promoters and enhancers, where we found a selective gain of the mark, suggestive of a directed silencing. In contrast, poised TSSs lose H3K27me3 and gain the activation mark H3K27ac, reflecting potential activation. Taken together, we present a comprehensive map of the epigenomic changes in MM as compared to NPC and provide insights into the interplay between EZH2 and DNMT1 in MM.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Multiple myeloma
- DNA methylation
- H3K27me3
- 5-azacytidine
- UNC1999.
Publication and Content Type
- vet (subject category)
- ovr (subject category)
To the university's database
- By the author/editor
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Atienza-Párraga, ...
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Diamanti, Klev
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Nylund, Patrick
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Skaftason, Aron
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Ma, Anqi
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Jin, Jian
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show more...
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Martín-Subero, J ...
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Öberg, Fredrik
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Komorowski, Jan
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Jernberg-Wiklund ...
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Kalushkova, Anto ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- By the university
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Uppsala University