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Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer

Aberrant DNA methylation is an early event in breast carcinogenesis and plays a critical role in regulating gene expression. Here, we perform genome-wide expression-methylation Quantitative Trait Loci (emQTL) analysis through the integration of DNA methylation and gene expression to identify disease...

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Autores principales: Ankill, Jørgen, Aure, Miriam Ragle, Bjørklund, Sunniva, Langberg, Severin, Kristensen, Vessela N, Vitelli, Valeria, Tekpli, Xavier, Fleischer, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8947789/
https://www.ncbi.nlm.nih.gov/pubmed/35350772
http://dx.doi.org/10.1093/narcan/zcac008
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author Ankill, Jørgen
Aure, Miriam Ragle
Bjørklund, Sunniva
Langberg, Severin
Kristensen, Vessela N
Vitelli, Valeria
Tekpli, Xavier
Fleischer, Thomas
author_facet Ankill, Jørgen
Aure, Miriam Ragle
Bjørklund, Sunniva
Langberg, Severin
Kristensen, Vessela N
Vitelli, Valeria
Tekpli, Xavier
Fleischer, Thomas
author_sort Ankill, Jørgen
collection PubMed
description Aberrant DNA methylation is an early event in breast carcinogenesis and plays a critical role in regulating gene expression. Here, we perform genome-wide expression-methylation Quantitative Trait Loci (emQTL) analysis through the integration of DNA methylation and gene expression to identify disease-driving pathways under epigenetic control. By grouping the emQTLs using biclustering we identify associations representing important biological processes associated with breast cancer pathogenesis including regulation of proliferation and tumor-infiltrating fibroblasts. We report genome-wide loss of enhancer methylation at binding sites of proliferation-driving transcription factors including CEBP-β, FOSL1, and FOSL2 with concomitant high expression of proliferation-related genes in aggressive breast tumors as we confirm with scRNA-seq. The identified emQTL-CpGs and genes were found connected through chromatin loops, indicating that proliferation in breast tumors is under epigenetic regulation by DNA methylation. Interestingly, the associations between enhancer methylation and proliferation-related gene expression were also observed within known subtypes of breast cancer, suggesting a common role of epigenetic regulation of proliferation. Taken together, we show that proliferation in breast cancer is linked to loss of methylation at specific enhancers and transcription factor binding and gene activation through chromatin looping.
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spelling pubmed-89477892022-03-28 Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer Ankill, Jørgen Aure, Miriam Ragle Bjørklund, Sunniva Langberg, Severin Kristensen, Vessela N Vitelli, Valeria Tekpli, Xavier Fleischer, Thomas NAR Cancer Cancer Gene Regulation, Chromatin, and Epigenetics Aberrant DNA methylation is an early event in breast carcinogenesis and plays a critical role in regulating gene expression. Here, we perform genome-wide expression-methylation Quantitative Trait Loci (emQTL) analysis through the integration of DNA methylation and gene expression to identify disease-driving pathways under epigenetic control. By grouping the emQTLs using biclustering we identify associations representing important biological processes associated with breast cancer pathogenesis including regulation of proliferation and tumor-infiltrating fibroblasts. We report genome-wide loss of enhancer methylation at binding sites of proliferation-driving transcription factors including CEBP-β, FOSL1, and FOSL2 with concomitant high expression of proliferation-related genes in aggressive breast tumors as we confirm with scRNA-seq. The identified emQTL-CpGs and genes were found connected through chromatin loops, indicating that proliferation in breast tumors is under epigenetic regulation by DNA methylation. Interestingly, the associations between enhancer methylation and proliferation-related gene expression were also observed within known subtypes of breast cancer, suggesting a common role of epigenetic regulation of proliferation. Taken together, we show that proliferation in breast cancer is linked to loss of methylation at specific enhancers and transcription factor binding and gene activation through chromatin looping. Oxford University Press 2022-03-24 /pmc/articles/PMC8947789/ /pubmed/35350772 http://dx.doi.org/10.1093/narcan/zcac008 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Cancer Gene Regulation, Chromatin, and Epigenetics
Ankill, Jørgen
Aure, Miriam Ragle
Bjørklund, Sunniva
Langberg, Severin
Kristensen, Vessela N
Vitelli, Valeria
Tekpli, Xavier
Fleischer, Thomas
Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer
title Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer
title_full Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer
title_fullStr Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer
title_full_unstemmed Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer
title_short Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer
title_sort epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer
topic Cancer Gene Regulation, Chromatin, and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8947789/
https://www.ncbi.nlm.nih.gov/pubmed/35350772
http://dx.doi.org/10.1093/narcan/zcac008
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