Journal Article

Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics

Catovsky, Daniel, Beà, Sílvia, Houlston, Richard S., Gutiérrez-Abril, Jesús, Speedy, Helen E., Martín-García, David, Martín-Subero, José I., Clot, Guillem, Puiggròs, Montserrat, Beekman, Renée, Law, Philip J., Chapaprieta, Vicente, Orlando, Giulia, Torrents, David, Puente, Xose S., Allan, James M., López-Otín, Carlos, Campo, Elias

2019

Overview

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL. The definition of regulatory landscape at chronic lymphocytic leukaemia (CLL) risk loci is limited. Here, the authors perform an epigenomic characterisation of 42 known risk loci in CLL and normal B cells at different developmental stages and show active chromatin and target genes in the risk loci.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/208/205/2138 / 631/67/1990/283/1895 / 631/67/68/2486 / B-Lymphocytes - metabolism / Base Sequence / Chromatin / Chromatin - metabolism / Chronic lymphocytic leukemia / Deoxyribonucleic acid / DNA / DNA Methylation / Epigenesis, Genetic - genetics / Epigenesis, Genetic - physiology / Epigenetics / Epigenomics / Gene expression / Gene Expression Regulation, Leukemic / Genes / Genetic analysis / Genetic Predisposition to Disease - genetics / Genome-wide association studies / Genome-Wide Association Study / Genomes / Genotype / Humanities and Social Sciences / Humans / Leukemia / Leukemia, Lymphocytic, Chronic, B-Cell - genetics / Leukemia, Lymphocytic, Chronic, B-Cell - metabolism / Loci / Lymphatic leukemia / Lymphocytes B / multidisciplinary / Myc protein / Polymorphism, Single Nucleotide / Promoter Regions, Genetic / Proto-Oncogene Proteins c-bcl-2 - metabolism / Proto-Oncogene Proteins c-myc - metabolism / Regulatory sequences / Risk analysis / Science / Science (multidisciplinary) / Signal transduction / Transcription Factors