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.

The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability

“…Furthermore, we showed that DNA hypomethylation is variable within the myeloma cells of one individual and that methylation loss modifies H3K27me3 distribution across patients; we can hypothesize that H3K27me3 redistribution is heterogeneous among myeloma cells, leading to cell-to-cell epigenetic variability. Consequently, the tumoral mass in a MM patient would be composed of an admixture of myeloma cells with divergent epigenetic identities, in accordance with what has been demonstrated recently in CLL [56].…”

Epigenomically Bistable Regions across Neuron-Specific Genes Govern Neuron Eligibility to a Coding Ensemble in the Hippocampus

“…Plates were stored at −80°C. Processing of samples were as described for Multiplexed single-cell RRBS ( Pastore et al, 2019 ) by the Epigenomic Core Facility of Weill Cornell Medicine. Briefly, nuclei were lysed, DNA was cut with Msp1 (Fermentas), and A-tailed DNA fragments were ligated with custom methylated adapters containing inline cell barcodes.…”

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

“…7,71 Several groups have evaluated the full reference epigenome of CLL, providing a genome-wide map of histone marks and three-dimensional chromatin architecture. 6,[72][73][74] Surprisingly, there was a significant variability in active regulatory regions among individual patients. This variability, and also the total number of active sites, was larger in U-CLL than in M-CLL.…”