Linking aberrant chromatin features in chronic lymphocytic leukemia to deregulated transcription factor networks

In chronic lymphocytic leukemia (CLL) a diverse set of genetic mutations is embedded in a deregulated epigenetic landscape that drives cancerogenesis. To elucidate the role of aberrant chromatin features, we mapped DNA methylation, 7 histone modifications, nucleosome positions, chromatin accessibility, binding of EBF1 and CTCF as well as the transcriptome of B cells from CLL patients and healthy donors. A globally increased histone deacetylase activity was detected and half of the genome comprised transcriptionally downregulated partially DNA methylated domains demarcated by CTCF. CLL samples displayed a H3K4me3 redistribution and nucleosome gain at promoters as well as changes of enhancer activity and enhancer linkage to target genes. A DNA binding motif analysis identified transcription factors that gained or lost binding in CLL at sites with aberrant chromatin features. These findings were integrated into a gene regulatory enhancer containing network enriched for B cell receptor signaling pathway components. Our study predicts novel molecular links to targets of CLL therapies and provides a valuable resource for further studies on the epigenetic contribution to the disease. Mallm JP, Iskar M, Ishaque N, Klett LC, Kugler SJ, Muino JM, Teif VB, Poos AM, Großmann S, Erdel F, Tavernari D, Koser SD, Schumacher S, Brors B, König R, Remondini D, Vingron M, Stilgenbauer S, Lichter P, Zapatka M, Mertens D & Rippe K (2019) Linking aberrant chromatin features in chronic lymphocytic leukemia to deregulated transcription factor networks. Mol Syst Biol 15, e8339. doi: 10.15252/msb.20188339 We analyzed a carefully selected cohort of clinically and genetically fully characterized primary leukemia cells in bulk samples and at the single cell level for genome-wide DNA-methylation, nucleosome position, DNA-accessibility by ATAC-seq, the 7 most relevant histone modifications plus CTCF and EBF1 by ChIPseq as well as the transcriptome. Raw sequencing data for all the samples are available at the European Genome-phenome Archive (http://www.ebi.ac.uk/ega/), under the accession number EGAS00001002518.