Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics.
B-Lymphocytes
/ metabolism
Base Sequence
Chromatin
/ metabolism
DNA Methylation
Epigenesis, Genetic
/ genetics
Epigenomics
Gene Expression Regulation, Leukemic
Genetic Predisposition to Disease
/ genetics
Genome-Wide Association Study
Genotype
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
/ genetics
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Proto-Oncogene Proteins c-bcl-2
/ metabolism
Proto-Oncogene Proteins c-myc
/ metabolism
Transcription Factors
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
09 08 2019
09 08 2019
Historique:
received:
13
07
2018
accepted:
23
07
2019
entrez:
11
8
2019
pubmed:
11
8
2019
medline:
18
12
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31399598
doi: 10.1038/s41467-019-11582-2
pii: 10.1038/s41467-019-11582-2
pmc: PMC6689100
doi:
Substances chimiques
BCL2 protein, human
0
Chromatin
0
MYC protein, human
0
Proto-Oncogene Proteins c-bcl-2
0
Proto-Oncogene Proteins c-myc
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3615Subventions
Organisme : Blood Cancer UK
ID : 06002
Pays : United Kingdom
Organisme : Blood Cancer UK
ID : 13044
Pays : United Kingdom
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