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

Mallm, Jan Philipp and Iskar, Murat and Ishaque, Naveed and Klett, Lara C and Kugler, Sabrina J and Muino, Jose M and Teif, Vladimir B and Poos, Alexandra M and Großmann, Sebastian and Erdel, Fabian and Tavernari, Daniele and Koser, Sandra D and Schumacher, Sabrina and Brors, Benedikt and König, Rainer and Remondini, Daniel and Vingron, Martin and Stilgenbauer, Stephan and Lichter, Peter and Zapatka, Marc and Mertens, Daniel and Rippe, Karsten (2019) 'Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks.' Molecular Systems Biology, 15 (5). ISSN 1744-4292

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Abstract

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, seven 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.

Item Type: Article
Uncontrolled Keywords: CLL, epigenetics, chromatin, transcription factors, cancer
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Elements
Date Deposited: 12 Jun 2019 13:32
Last Modified: 14 Aug 2019 15:15
URI: http://repository.essex.ac.uk/id/eprint/24754

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