Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks

Abstract

Chronic lymphocytic leukaemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, here we present genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients measured by the ATAC-seq assay. We also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting data set, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status—which distinguishes the two major subtypes of CLL—was accurately predicted by the chromatin profiles and gene regulatory networks inferred for IGHV-mutated versus IGHV-unmutated samples identified characteristic differences between these two disease subtypes. In summary, we discovered widespread heterogeneity in the chromatin landscape of CLL, established a community resource for studying epigenome deregulation in leukaemia and demonstrated the feasibility of large-scale chromatin accessibility mapping in cancer cohorts and clinical research.

The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery

“…Epigenomic profiles of normal cell types also provide a valuable comparator for their counterparts in diseased tissues. Such comparisons have been performed in solid tumors such as breast cancer (Hirst and Eaves 2016) and extra-cranial malignant rhabdoid tumors (Chun, Lim et al 2016), hematological neoplasms such as mantle cell lymphoma (Martín-Subero 2016) and chronic lymphocytic leukemia (Rendeiro, Schmidl et al 2016). These analyses have not only provided unprecedented insights into disease pathogenesis but have also enabled the stratification of diseases into novel clinico-biological subtypes.…”

ALTRE: workflow for defining ALTered Regulatory Elements using chromatin accessibility data

“…Organization of these REs, particularly enhancers, is cell-type specific (Kieffer-Kwon et al , 2013; Rendeiro et al , 2016; Stergachis et al , 2013) and is a strong determinant of disease mutational landscapes, including those of cancer (Polak et al , 2015). Thus, identifying REs that differ in accessibility between cell types, such as cancerous and non-cancerous cell lines and tissues, holds promise for pinpointing mechanisms involved in disease progression.…”

Non-coding genetic variation in cancer

“…This makes it hard to obtain an accurate map of epigenetic states in cancer samples, which is essential for understanding the impact of non-coding genetic variants on rewiring of the regulatory network as cells transform from normal to malignant state. Creation of the tumor-specific epigenetic maps with new technologies (such as Assay for Transposase Accessible Chromatin using sequencing (ATAC-seq) [55,56]) holds the promise to bridge this gap and allow a more complete understanding of the role of non-coding regions in cancer.…”