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

   

Authors:	Pastore, A.; Gaiti, F.; Lu, S. X.; Brand, R. M.; Kulm, S.; Chaligne, R.; Gu, H.; Huang, K. Y.; Stamenova, E. K.; Béguelin, W.; Jiang, Y.; Schulman, R. C.; Kim, K. T.; Alonso, A.; Allan, J. N.; Furman, R. R.; Gnirke, A.; Wu, C. J.; Melnick, A. M.; Meissner, A.; Bernstein, B. E.; Abdel-Wahab, O.; Landau, D. A.
Article Title:	Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL
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. © 2019, The Author(s).
Keywords:	clinical article; gene mutation; methylation; genetic analysis; polymerase chain reaction; protein motif; lymphocyte proliferation; gene overexpression; gene expression; protein; cohort analysis; genetic variability; transcription factor; immunoglobulin enhancer binding protein; genetic transcription; dna methylation; sequence alignment; epigenetics; chromatin immunoprecipitation; genome; upregulation; gene regulatory network; gene silencing; chronic lymphatic leukemia; cd5 antigen; transcriptome; dna determination; oncogene myc; cd27 antigen; genetic heterogeneity; rna sequence; pigment; heterogeneity; wnt signaling; histone modification; hidden markov model; genetic transformation; chromatin condensation; cd23 antigen; b lymphocyte receptor; cd20 antibody; entropy; polycomb repressive complex 2; mapk signaling; cd19 antibody; genotyping technique; cancer; human; article; whole exome sequencing; immunoglobulin d antibody; chromosomal mapping; adp ribosyl cyclase/cyclic adp ribose hydrolase 1; mrna expression level
Journal Title:	Nature Communications
Volume:	10
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2019-04-23
Start Page:	1874
Language:	English
DOI:	10.1038/s41467-019-09645-5
PUBMED:	31015400
PROVIDER:	scopus
PMCID:	PMC6478836
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85064904728&doi=10.1038%2fs41467-019-09645-5&partnerID=40&md5=84705769d012ec35c725539c6a72eac2
Notes:	Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/146436