Format

Send to

Choose Destination
Nat Commun. 2019 Apr 23;10(1):1874. doi: 10.1038/s41467-019-09645-5.

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

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
2
New York Genome Center, New York, 10013, NY, USA.
3
Weill Cornell Medicine, New York, 10021, NY, USA.
4
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, 10021, NY, USA.
5
Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA.
6
Dana-Farber Cancer Institute, Boston, 02215, MA, USA.
7
Max Planck Institute for Molecular Genetics, Berlin, 14195, Germany.
8
Department of Pathology, Massachusetts General Hospital, Boston, 02114, MA, USA.
9
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA. abdelwao@mskcc.org.
10
Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA. abdelwao@mskcc.org.
11
New York Genome Center, New York, 10013, NY, USA. dlandau@nygenome.org.
12
Weill Cornell Medicine, New York, 10021, NY, USA. dlandau@nygenome.org.
13
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, 10021, NY, USA. dlandau@nygenome.org.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center