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Nat Commun. 2017 Nov 9;8(1):1379. doi: 10.1038/s41467-017-00510-x.

DNA methylation at enhancers identifies distinct breast cancer lineages.

Author information

1
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
2
Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University hospital, Division of Medicine, Lørenskog, Norway.
3
Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway.
4
Department of Pathology, Oslo University Hospital, Oslo, Norway.
5
Department of Research, Vestre Viken Hospital Trust, Drammen, Norway.
6
Department of Oncology, Oslo University Hospital, Oslo, Norway.
7
Department of Biosciences, University of Oslo, Oslo, Norway.
8
Department of Immunology, Norwegian Center for Stem Cell Research, Oslo University Hospital, Oslo, Norway.
9
Department of Biostatistics, Oslo Centre for Biostatistics and Epidemiology, University of Oslo and Research Support Services, Oslo University Hospital, Oslo, Norway.
10
Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France.
11
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway. Vessela.N.Kristensen@rr-research.no.
12
Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University hospital, Division of Medicine, Lørenskog, Norway. Vessela.N.Kristensen@rr-research.no.
13
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Vessela.N.Kristensen@rr-research.no.

Abstract

Breast cancers exhibit genome-wide aberrant DNA methylation patterns. To investigate how these affect the transcriptome and which changes are linked to transformation or progression, we apply genome-wide expression-methylation quantitative trait loci (emQTL) analysis between DNA methylation and gene expression. On a whole genome scale, in cis and in trans, DNA methylation and gene expression have remarkably and reproducibly conserved patterns of association in three breast cancer cohorts (n = 104, n = 253 and n = 277). The expression-methylation quantitative trait loci associations form two main clusters; one relates to tumor infiltrating immune cell signatures and the other to estrogen receptor signaling. In the estrogen related cluster, using ChromHMM segmentation and transcription factor chromatin immunoprecipitation sequencing data, we identify transcriptional networks regulated in a cell lineage-specific manner by DNA methylation at enhancers. These networks are strongly dominated by ERα, FOXA1 or GATA3 and their targets were functionally validated using knockdown by small interfering RNA or GRO-seq analysis after transcriptional stimulation with estrogen.

PMID:
29123100
PMCID:
PMC5680222
DOI:
10.1038/s41467-017-00510-x
[Indexed for MEDLINE]
Free PMC Article

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