TitleCorrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL.
Publication TypeJournal Article
Year of Publication2019
AuthorsPastore, Alessandro, Gaiti Federico, Lu Sydney X., Brand Ryan M., Kulm Scott, Chaligne Ronan, Gu Hongcang, Huang Kevin Y., Stamenova Elena K., Béguelin Wendy, Jiang Yanwen, Schulman Rafael C., Kim Kyu-Tae, Alonso Alicia, Allan John N., Furman Richard R., Gnirke Andreas, Wu Catherine J., Melnick Ari M., Meissner Alexander, Bernstein Bradley E., Abdel-Wahab Omar, and Landau Dan A.
JournalNat Commun
Date Published2019 Apr 23
KeywordsB-Lymphocytes, Chromatin, DNA Methylation, Epigenesis, Genetic, Evolution, Molecular, Exome Sequencing, Gene Expression Regulation, Neoplastic, Gene Silencing, Genes, Immunoglobulin Heavy Chain, Healthy Volunteers, Histone Code, Histones, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Polycomb-Group Proteins, Promoter Regions, Genetic, Sequence Analysis, RNA, Single-Cell Analysis

<p>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.</p>

Alternate JournalNat Commun
PubMed ID31015400
PubMed Central IDPMC6478836
Grant ListR35 CA220499 / CA / NCI NIH HHS / United States
R01 CA216273 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
K01 ES025431 / ES / NIEHS NIH HHS / United States
R01 HL145283 / HL / NHLBI NIH HHS / United States
UG1 CA233338 / CA / NCI NIH HHS / United States
R01 CA229902 / CA / NCI NIH HHS / United States
DP2 CA239065 / CA / NCI NIH HHS / United States