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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.

SUBMITTER: Pastore A

PROVIDER: S-EPMC6478836 | biostudies-other | 2019 Apr

REPOSITORIES: biostudies-other

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

Pastore Alessandro A Gaiti Federico F Lu Sydney X SX Brand Ryan M RM Kulm Scott S Chaligne Ronan R Gu Hongcang H Huang Kevin Y KY Stamenova Elena K EK Béguelin Wendy W Jiang Yanwen Y Schulman Rafael C RC Kim Kyu-Tae KT Alonso Alicia A Allan John N JN Furman Richard R RR Gnirke Andreas A Wu Catherine J CJ Melnick Ari M AM Meissner Alexander A Bernstein Bradley E BE Abdel-Wahab Omar O Landau Dan A DA

Nature communications 20190423 1

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 th ...[more]

PMID: 31015400

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Project description:Gene regulation often appears deterministic in the average cell population, but transcription is a probabilistic process at the single-cell level. Although many mechanisms are invoked to account for this behavior, it is difficult to determine how cell-to-cell variation in the interactions of transcription factors with target chromatin impact transcriptional output. Here, we use cells that contain a 200-copy tandem array of promoter or reporter gene units to simultaneously visualize transient interaction, equilibrium or steady-state binding of fluorescent-protein-labeled glucocorticoid receptor with its DNA response elements, the recruitment of diverse coregulators, and transcriptional output at the single-cell level. These regulatory proteins associate with target chromatin via a probabilistic mechanism that produces cell-to-cell variability in binding. The multiple steps of this process are partially independent and differ between individual regulators. The association level of each regulator influences the transcriptional output in individual cells, but this does not account for all transcriptional heterogeneity. Additionally, specific combinatorial interactions of the glucocorticoid receptor and coregulators with response elements regulate transcription at the single-cell level. Like many endogenous genes, the average array transcriptional activity evolves over time. This apparently deterministic average temporal promoter progression involves changes in the probability that specific combinatorial glucocorticoid receptor and coregulator interactions will occur on the response elements in single cells. These data support the emerging ;return-to-template' transcription model, which mechanistically unifies the observed extremely transient interactions between the transcription factor and response elements, cell-to-cell variability in steady-state association of factors with chromatin, and the resulting heterogeneous gene expression between individual cells.

Dataset Information

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

Publications

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

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