Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics.
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Date
2019-08-09Author
Speedy, HE
Beekman, R
Chapaprieta, V
Orlando, G
Law, PJ
Martín-García, D
Gutiérrez-Abril, J
Catovsky, D
Beà, S
Clot, G
Puiggròs, M
Torrents, D
Puente, XS
Allan, JM
López-Otín, C
Campo, E
Houlston, RS
Martín-Subero, JI
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
B-Lymphocytes
Chromatin
Humans
Genetic Predisposition to Disease
Proto-Oncogene Proteins c-myc
Proto-Oncogene Proteins c-bcl-2
Transcription Factors
DNA Methylation
Epigenesis, Genetic
Gene Expression Regulation, Leukemic
Base Sequence
Genotype
Polymorphism, Single Nucleotide
Leukemia, Lymphocytic, Chronic, B-Cell
Promoter Regions, Genetic
Genome-Wide Association Study
Epigenomics
Research team
Cancer Genomics
Language
eng
Date accepted
2019-07-23
License start date
2019-08-09
Citation
Nature communications, 2019, 10 (1), pp. 3615 - ?
Publisher
NATURE PUBLISHING GROUP