Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics.
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Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2019-08-09
Date Accepted
2019-07-23
Abstract
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.
Citation
Nature communications, 2019, 10 (1), pp. 3615 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Cancer Genomics