期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09645-5
关键词
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资金
- Mildred-Scheel Postdoctoral Research Fellowship of the Deutsche Krebshilfe e.V.
- AACR fellowship
- LRF fellowship
- Marie Sklodowska-Curie fellowship
- Broad Institute SPARC
- Burroughs Wellcome Fund Career Award for Medical Scientists
- ASH Scholar Award
- Pershing Square Sohn Prize for Young Investigators in Cancer Research
- NIH Director's New Innovator Award [DP2-CA239065]
- Starr Foundation
- Max Planck Society
- LLS Translational Research Program
- National Cancer Institute [R01-CA229902]
- Stand Up To Cancer Innovative Research Grant [SU2C-AACR-IRG-0616]
Cancer evolution is fueled by epigenetic as well as genetic diversity. In chronic lymphocytic leukemia (CLL), intra-tumoral DNA methylation (DNAme) heterogeneity empowers evolution. Here, to comprehensively study the epigenetic dimension of cancer evolution, we integrate DNAme analysis with histone modification mapping and single cell analyses of RNA expression and DNAme in 22 primary CLL and 13 healthy donor B lymphocyte samples. Our data reveal corrupted coherence across different layers of the CLL epigenome. This manifests in decreased mutual information across epigenetic modifications and gene expression attributed to cell-to-cell heterogeneity. Disrupted epigenetic-transcriptional coordination in CLL is also reflected in the dysregulation of the transcriptional output as a function of the combinatorial chromatin states, including incomplete Polycomb-mediated gene silencing. Notably, we observe unexpected co-mapping of typically mutually exclusive activating and repressing histone modifications, suggestive of intra-tumoral epigenetic diversity. Thus, CLL epigenetic diversification leads to decreased coordination across layers of epigenetic information, likely reflecting an admixture of cells with diverging cellular identities.
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