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Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL.
- Source :
-
Nature communications [Nat Commun] 2019 Apr 23; Vol. 10 (1), pp. 1874. Date of Electronic Publication: 2019 Apr 23. - Publication Year :
- 2019
-
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.
- Subjects :
- DNA Methylation
Evolution, Molecular
Gene Silencing
Genes, Immunoglobulin Heavy Chain genetics
Healthy Volunteers
Histone Code genetics
Histones genetics
Histones metabolism
Humans
Leukemia, Lymphocytic, Chronic, B-Cell blood
Polycomb-Group Proteins genetics
Polycomb-Group Proteins metabolism
Promoter Regions, Genetic genetics
Sequence Analysis, RNA
Single-Cell Analysis methods
Exome Sequencing
B-Lymphocytes metabolism
Chromatin metabolism
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Leukemia, Lymphocytic, Chronic, B-Cell genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 31015400
- Full Text :
- https://doi.org/10.1038/s41467-019-09645-5