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Expression of ncRNAs on the DLK1-DIO3 Locus Is Associated With Basal and Mesenchymal Phenotype in Breast Epithelial Progenitor Cells

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dc.contributor Háskóli Íslands
dc.contributor University of Iceland
dc.contributor.author Budkova, Zuzana
dc.contributor.author Sigurðardóttir, Anna Karen
dc.contributor.author Briem, Eiríkur
dc.contributor.author Bergthorsson, Jon Thor
dc.contributor.author Sigurðsson, Snævar
dc.contributor.author Magnusson, Magnus Karl
dc.contributor.author Traustadottir, Gunnhildur Asta
dc.contributor.author Gudjonsson, Thorarinn
dc.contributor.author Hilmarsdóttir, Bylgja
dc.date.accessioned 2020-12-21T13:47:36Z
dc.date.available 2020-12-21T13:47:36Z
dc.date.issued 2020-06-16
dc.identifier.citation Citation: Budkova Z, Sigurdardottir AK, Briem E, Bergthorsson JT, Sigurdsson S, Magnusson MK, Traustadottir GA, Gudjonsson T and Hilmarsdottir B (2020) Expression of ncRNAs on the DLK1-DIO3 Locus Is Associated With Basal and Mesenchymal Phenotype in Breast Epithelial Progenitor Cells. Frontiers in Cell and Developmental Biology 8:461. doi: 10.3389/fcell.2020.00461
dc.identifier.issn 2296-634X
dc.identifier.uri https://hdl.handle.net/20.500.11815/2318
dc.description Publisher's version (útgefin grein)
dc.description.abstract Epithelial-to-mesenchymal transition (EMT) and its reversed process mesenchymal-to-epithelial transition (MET) play a critical role in epithelial plasticity during development and cancer progression. Among important regulators of these cellular processes are non-coding RNAs (ncRNAs). The imprinted DLK1-DIO3 locus, containing numerous maternally expressed ncRNAs including the lncRNA maternally expressed gene 3 (MEG3) and a cluster of over 50 miRNAs, has been shown to be a modulator of stemness in embryonic stem cells and in cancer progression, potentially through the tumor suppressor role of MEG3. In this study we analyzed the expression pattern and functional role of ncRNAs from the DLK1-DIO3 locus in epithelial plasticity of the breast. We studied their expression in various cell types of breast tissue and revisit the role of the locus in EMT/MET using a breast epithelial progenitor cell line (D492) and its isogenic mesenchymal derivative (D492M). Marked upregulation of ncRNAs from the DLK1-DIO3 locus was seen after EMT induction in two cell line models of EMT. In addition, the expression of MEG3 and the maternally expressed ncRNAs was higher in stromal cells compared to epithelial cell types in primary breast tissue. We also show that expression of MEG3 is concomitant with the expression of the ncRNAs from the DLK1-DIO3 locus and its expression is therefore likely indicative of activation of all ncRNAs at the locus. MEG3 expression is correlated with stromal markers in normal tissue and breast cancer tissue and negatively correlated with the survival of breast cancer patients in two different cohorts. Overexpression of MEG3 using CRISPR activation in a breast epithelial cell line induced partial EMT and enriched for a basal-like phenotype. Conversely, knock down of MEG3 using CRISPR inhibition in a mesenchymal cell line reduced the mesenchymal and basal-like phenotype of the cell line. In summary our study shows that maternally expressed ncRNAs are markers of EMT and suggests that MEG3 is a novel regulator of EMT/MET in breast tissue. Nevertheless, further studies are needed to fully dissect the molecular pathways influenced by non-coding RNAs at the DLK1-DIO3 locus in breast tissue.
dc.description.sponsorship This work was supported by Grants from Landspitali University Hospital Science Fund, University of Iceland Research Fund, Icelandic Science and Technology Policy Council Research Fund no. 1103010061, Icelandic Science and Technology Policy – Grant of Excellence: 52144051, “Vísindasjóður Krabbameinsfélagsins” (Icelandic Cancer Society Science Fund) 2017 and ‘Göngum saman’, a supporting group for breast cancer research in Iceland (www.gongumsaman.is). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
dc.format.extent 461
dc.language.iso en
dc.publisher Frontiers Media SA
dc.relation.ispartofseries Frontiers in Cell and Developmental Biology;8
dc.rights info:eu-repo/semantics/openAccess
dc.subject Breast progenitor cells
dc.subject DLK1-DIO3 locus
dc.subject Epithelial plasticity
dc.subject MEG3
dc.subject ncRNAs
dc.subject Brjóstakrabbamein
dc.subject DNA-rannsóknir
dc.title Expression of ncRNAs on the DLK1-DIO3 Locus Is Associated With Basal and Mesenchymal Phenotype in Breast Epithelial Progenitor Cells
dc.type info:eu-repo/semantics/article
dcterms.license This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
dc.description.version Peer Reviewed
dc.identifier.journal Frontiers in Cell and Developmental Biology
dc.identifier.doi 10.3389/fcell.2020.00461
dc.relation.url https://www.frontiersin.org/article/10.3389/fcell.2020.00461/full
dc.contributor.department Læknadeild (HÍ)
dc.contributor.department Faculty of Medicine (UI)
dc.contributor.department Lífvísindasetur (HÍ)
dc.contributor.department Biomedical Center (UI)
dc.contributor.school Heilbrigðisvísindasvið (HÍ)
dc.contributor.school School of Health Sciences (UI)

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