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.
Highlights
Cancer evolution is fueled by epigenetic as well as genetic diversity
As ChIP-seq experiments are prone to technical variation, we further demonstrated the reproducibility of H3K27ac derangements in chronic lymphocytic leukemia (CLL) by analyzing additional CLL and normal B cell samples from the Blueprint Initiative[18] (Supplementary Data 1), showing high pairwise correlations across our cohort and the Blueprint initiative samples at super-enhancers (Supplementary Fig. 1e)
In line with prior studies that profiled epigenomic features of a large CLL cohort and discrete normal B cell subtypes along the differentiation program[8,19], this extensive chromatin rewiring at super-enhancers is mediated by specific transcription factors, as evidenced by enrichment of their motifs in activated super-enhancers, including NFAT, a deregulated gene with functional and therapeutic potential in CLL8, and TCFL2, a downstream target of the WNT pathway overexpressed in CLL20 (Fig. 1e, f; Supplementary Data 2, 3)
Summary
Cancer evolution is fueled by epigenetic as well as genetic diversity. In chronic lymphocytic leukemia (CLL), intra-tumoral DNA methylation (DNAme) heterogeneity empowers evolution. 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. Given the importance of histone modifications to lineage plasticity in cancer[11,12], we reasoned that intra-leukemic epigenetic heterogeneity may extend to histone modifications, likely promoting lineage plasticity by enabling permissive chromatin states To address this question, we complemented bulk reduced representation bisulfite sequencing (RRBS) analysis with a chromatin immunoprecipitation sequencing (ChIP-seq) compendium of histone post-translational modifications and gene expression, together with joint DNAme and transcriptome single cell analysis in a cohort of 22 primary CLL and 13 healthy B lymphocytes samples. Our integrative analysis revealed a markedly decreased coordination between different layers of the CLL epigenome, whereby ongoing epigenetic diversification leads to an admixture of cells with diverging epigenetic identities, providing a novel perspective into the epigenetic dimension of cancer evolution
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