Cargando…

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

BACKGROUND: Abnormal 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 inte...

Descripción completa

Detalles Bibliográficos
Autores principales: Aure, Miriam Ragle, Fleischer, Thomas, Bjørklund, Sunniva, Ankill, Jørgen, Castro-Mondragon, Jaime A., Børresen-Dale, Anne-Lise, Tost, Jörg, Sahlberg, Kristine K., Mathelier, Anthony, Tekpli, Xavier, Kristensen, Vessela N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086068/
https://www.ncbi.nlm.nih.gov/pubmed/33926515
http://dx.doi.org/10.1186/s13073-021-00880-4
_version_ 1783686452007141376
author Aure, Miriam Ragle
Fleischer, Thomas
Bjørklund, Sunniva
Ankill, Jørgen
Castro-Mondragon, Jaime A.
Børresen-Dale, Anne-Lise
Tost, Jörg
Sahlberg, Kristine K.
Mathelier, Anthony
Tekpli, Xavier
Kristensen, Vessela N.
author_facet Aure, Miriam Ragle
Fleischer, Thomas
Bjørklund, Sunniva
Ankill, Jørgen
Castro-Mondragon, Jaime A.
Børresen-Dale, Anne-Lise
Tost, Jörg
Sahlberg, Kristine K.
Mathelier, Anthony
Tekpli, Xavier
Kristensen, Vessela N.
author_sort Aure, Miriam Ragle
collection PubMed
description BACKGROUND: Abnormal 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. METHODS: miRNA 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. RESULTS: Clustering 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. CONCLUSIONS: We describe how miRNA expression and DNA methylation interact and associate with distinct breast cancer phenotypes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00880-4.
format Online
Article
Text
id pubmed-8086068
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-80860682021-04-30 Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer Aure, Miriam Ragle Fleischer, Thomas Bjørklund, Sunniva Ankill, Jørgen Castro-Mondragon, Jaime A. Børresen-Dale, Anne-Lise Tost, Jörg Sahlberg, Kristine K. Mathelier, Anthony Tekpli, Xavier Kristensen, Vessela N. Genome Med Research BACKGROUND: Abnormal 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. METHODS: miRNA 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. RESULTS: Clustering 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. CONCLUSIONS: We describe how miRNA expression and DNA methylation interact and associate with distinct breast cancer phenotypes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00880-4. BioMed Central 2021-04-29 /pmc/articles/PMC8086068/ /pubmed/33926515 http://dx.doi.org/10.1186/s13073-021-00880-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Aure, Miriam Ragle
Fleischer, Thomas
Bjørklund, Sunniva
Ankill, Jørgen
Castro-Mondragon, Jaime A.
Børresen-Dale, Anne-Lise
Tost, Jörg
Sahlberg, Kristine K.
Mathelier, Anthony
Tekpli, Xavier
Kristensen, Vessela N.
Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer
title Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer
title_full Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer
title_fullStr Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer
title_full_unstemmed Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer
title_short Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer
title_sort crosstalk between microrna expression and dna methylation drives the hormone-dependent phenotype of breast cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086068/
https://www.ncbi.nlm.nih.gov/pubmed/33926515
http://dx.doi.org/10.1186/s13073-021-00880-4
work_keys_str_mv AT auremiriamragle crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer
AT fleischerthomas crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer
AT bjørklundsunniva crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer
AT ankilljørgen crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer
AT castromondragonjaimea crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer
AT crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer
AT børresendaleannelise crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer
AT tostjorg crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer
AT sahlbergkristinek crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer
AT mathelieranthony crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer
AT tekplixavier crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer
AT kristensenvesselan crosstalkbetweenmicrornaexpressionanddnamethylationdrivesthehormonedependentphenotypeofbreastcancer