Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL

Alessandro Pastore, Federico Gaiti, Sydney X. Lu, Ryan M. Brand, Scott Kulm, Ronan Chaligne, Hongcang Gu, Kevin Y. Huang, Elena K. Stamenova, Wendy Béguelin, Yanwen Jiang, Rafael C. Schulman, Kyu-Tae Kim, Alicia Alonso, John N. Allan, Richard R. Furman, Andreas Gnirke, Catherine J. Wu, Ari M. Melnick, Alexander Meissner, Bradley E. Bernstein, Omar Abdel-Wahab () and Dan A. Landau ()
Additional contact information
Alessandro Pastore: Memorial Sloan Kettering Cancer Center
Federico Gaiti: New York Genome Center
Sydney X. Lu: Memorial Sloan Kettering Cancer Center
Ryan M. Brand: New York Genome Center
Scott Kulm: Weill Cornell Medicine
Ronan Chaligne: New York Genome Center
Hongcang Gu: Broad Institute of MIT and Harvard
Kevin Y. Huang: New York Genome Center
Elena K. Stamenova: Broad Institute of MIT and Harvard
Wendy Béguelin: Weill Cornell Medicine
Yanwen Jiang: Weill Cornell Medicine
Rafael C. Schulman: New York Genome Center
Kyu-Tae Kim: New York Genome Center
Alicia Alonso: Weill Cornell Medicine
John N. Allan: Weill Cornell Medicine
Richard R. Furman: Weill Cornell Medicine
Andreas Gnirke: Broad Institute of MIT and Harvard
Catherine J. Wu: Broad Institute of MIT and Harvard
Ari M. Melnick: Weill Cornell Medicine
Alexander Meissner: Broad Institute of MIT and Harvard
Bradley E. Bernstein: Broad Institute of MIT and Harvard
Omar Abdel-Wahab: Memorial Sloan Kettering Cancer Center
Dan A. Landau: New York Genome Center

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09645-5

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