Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer

Genome Medicine

Jaime A. Castro-Mondragon¹  Jørgen Ankill²  Thomas Fleischer²  Kristine K. Sahlberg³  Anne-Lise Børresen-Dale⁴  Miriam Ragle Aure⁵  Sunniva Bjørklund⁵  Xavier Tekpli⁵  Anthony Mathelier⁶  Vessela N. Kristensen⁷  Jörg Tost⁸ 

[1] Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, 0318, Oslo, Norway;Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0310, Oslo, Norway;Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0310, Oslo, Norway;Department of Research, Vestre Viken Hospital Trust, Drammen, Norway;Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0310, Oslo, Norway;Institute for Clinical Medicine, University of Oslo, Oslo, Norway;Department of Medical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway;Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0310, Oslo, Norway;Department of Medical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway;Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0310, Oslo, Norway;Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, 0318, Oslo, Norway;Department of Medical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway;Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0310, Oslo, Norway;Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Division of Medicine, Akershus University Hospital, Lørenskog, Norway;Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA–Institut de Biologie François Jacob, University Paris-Saclay, Evry, France;

关键词: miRNA;    Methylation;    Omics integration;    Breast cancer;    Systems biology;   

DOI  :  10.1186/s13073-021-00880-4

来源: Springer

【 摘 要 】

BackgroundAbnormal DNA methylation is observed as an early event in breast carcinogenesis. However, how such alterations arise is still poorly understood. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level and play key roles in various biological processes. Here, we integrate miRNA expression and DNA methylation at CpGs to study how miRNAs may affect the breast cancer methylome and how DNA methylation may regulate miRNA expression.MethodsmiRNA expression and DNA methylation data from two breast cancer cohorts, Oslo2 (n = 297) and The Cancer Genome Atlas (n = 439), were integrated through a correlation approach that we term miRNA-methylation Quantitative Trait Loci (mimQTL) analysis. Hierarchical clustering was used to identify clusters of miRNAs and CpGs that were further characterized through analysis of mRNA/protein expression, clinicopathological features, in silico deconvolution, chromatin state and accessibility, transcription factor binding, and long-range interaction data.ResultsClustering of the significant mimQTLs identified distinct groups of miRNAs and CpGs that reflect important biological processes associated with breast cancer pathogenesis. Notably, two major miRNA clusters were related to immune or fibroblast infiltration, hence identifying miRNAs associated with cells of the tumor microenvironment, while another large cluster was related to estrogen receptor (ER) signaling. Studying the chromatin landscape surrounding CpGs associated with the estrogen signaling cluster, we found that miRNAs from this cluster are likely to be regulated through DNA methylation of enhancers bound by FOXA1, GATA2, and ER-alpha. Further, at the hub of the estrogen cluster, we identified hsa-miR-29c-5p as negatively correlated with the mRNA and protein expression of DNA methyltransferase DNMT3A, a key enzyme regulating DNA methylation. We found deregulation of hsa-miR-29c-5p already present in pre-invasive breast lesions and postulate that hsa-miR-29c-5p may trigger early event abnormal DNA methylation in ER-positive breast cancer.ConclusionsWe describe how miRNA expression and DNA methylation interact and associate with distinct breast cancer phenotypes.

【 授权许可】

CC BY