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

Jan‐Philipp Mallm,Daniele Tavernari,Daniel Mertens,Fabian Erdel,Martin Vingron,Daniel Remondini,Marc Zapatka,Sabrina Schumacher,Alexandra M Poos,Sebastian Großmann,Stephan Stilgenbauer,Naveed Ishaque,Rainer König,Benedikt Brors,Murat Iskar,Peter Lichter,Karsten Rippe,Sabrina J Kugler ,Jose M Muiño ,Sandra D Koser ,Lara Klett ,Vladimir B Teif

doi:10.15252/msb.20188339

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.

Highlights

Genomic sequence analysis has identified a comprehensive set of leukemogenic candidate genes in chronic lymphocytic leukemia (CLL; Martin-Subero et al, 2013; Landau et al, 2015; Puente et al, 2015).10 Network Modeling, Leibniz Institute for Natural Product Research and Infection Biology—Hans Knöll Institute Jena, Jena, Germany11 Centre de Biologie Intégrative (CBI), CNRS, UPS, Toulouse, France12 Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany 13 Department of Physics and Astronomy, Bologna University, Bologna, Italy14 German Cancer Consortium (DKTK), Heidelberg, Germany a 2019 The Authors
While a number of pathophysiological processes such as microenvironmental signaling occur in secondary lymphoid organs of CLL patients (Burger & Gribben, 2014), the comprehensive analysis of different epigenetic layers required the acquisition of sufficient numbers of CD19+ B cells and was conducted from peripheral blood
Boundaries of partially methylated domains (PMDs) were enriched for occupied CTCF sites, which might indicate a role of CTCF to limit the expansion of PMDs

Summary

Introduction

CLL cells display a massive global transcriptional deregulation that is affecting intracellular pathways and microenvironmental signaling toward cellular survival (Burger & Chiorazzi, 2013) It appears that a diverse set of genetic lesions conspires with epigenetic aberrations to drive cancerogenesis in a manner that is only partially understood. The epigenetic subtypes of CLL defined by the DNA methylome may become important for patient stratification as they are of prognostic relevance (Queiros et al, 2015) These epigenetic subtypes are correlated with the two genetically defined subgroups of CLL that express a nonmutated or mutated immunoglobulin heavy-chain variable region gene (IGHV) and reflect the tumor cell of origin in an epigenetic continuum of B-cell development (Kulis et al, 2015; Oakes et al, 2016)

Methods

Results

Conclusion