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

Pastore, A., Gaiti, F., Lu, S. X., Brand, R. M., Kulm, S., Chaligne, R., et al. (2019). Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL. Nature Communications, 10(1): 1874. doi:10.1038/s41467-019-09645-5.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-904C-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-904D-4
Genre: Journal Article

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 Creators:
Pastore, Alessandro , Author
Gaiti, Federico , Author
Lu, Sydney X. , Author
Brand, Ryan M. , Author
Kulm, Scott , Author
Chaligne, Ronan , Author
Gu, Hongcang, Author
Huang, Kevin Y., Author
Stamenova, Elena K. , Author
Béguelin, Wendy , Author
Jiang, Yanwen , Author
chulman, Rafael C. , Author
Kim, Kyu-Tae , Author
Alonso, Alicia , Author
Allan, John N. , Author
Furman, Richard R. , Author
Gnirke, Andreas , Author
Wu, Catherine J. , Author
Melnick, Ari M. , Author
Meissner, Alexander1, 2, Author              
Bernstein, Bradley E. , AuthorAbdel-Wahab, Omar , AuthorLandau, Dan A. , Author more..
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA, ou_persistent22              

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Free keywords: Chronic lymphocytic leukaemia, Cancer epigenetics, Epigenomics, Gene regulation
 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.

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Language(s): eng - English
 Dates: 2019-03-222019-04-23
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/s41467-019-09645-5
 Degree: -

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 10 (1) Sequence Number: 1874 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723