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Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics

Lookup NU author(s): Professor James Allan

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Abstract

© 2019, The Author(s).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.

Publication metadata

Author(s): Speedy HE, Beekman R, Chapaprieta V, Orlando G, Law PJ, Martin-Garcia D, Gutierrez-Abril J, Catovsky D, Bea S, Clot G, Puiggros M, Torrents D, Puente XS, Allan JM, Lopez-Otin C, Campo E, Houlston RS, Martin-Subero JI

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2019

Volume: 10

Issue: 1

Online publication date: 09/08/2019

Acceptance date: 23/07/2019

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41467-019-11582-2

DOI: 10.1038/s41467-019-11582-2

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