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

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


Title: Expression of ncRNAs on the DLK1-DIO3 Locus Is Associated With Basal and Mesenchymal Phenotype in Breast Epithelial Progenitor Cells
Author: Budkova, Zuzana
Sigurðardóttir, Anna Karen
Briem, Eiríkur   orcid.org/0000-0001-7383-3570
Bergthorsson, Jon Thor   orcid.org/0000-0002-0560-2639
Sigurðsson, Snævar
Magnusson, Magnus Karl   orcid.org/0000-0001-8593-4934
Traustadottir, Gunnhildur Asta   orcid.org/0000-0001-6044-0989
Gudjonsson, Thorarinn   orcid.org/0000-0001-9645-9665
Hilmarsdóttir, Bylgja
Date: 2020-06-16
Language: English
Scope: 461
University/Institute: Háskóli Íslands
University of Iceland
School: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Department: Læknadeild (HÍ)
Faculty of Medicine (UI)
Lífvísindasetur (HÍ)
Biomedical Center (UI)
Series: Frontiers in Cell and Developmental Biology;8
ISSN: 2296-634X
DOI: 10.3389/fcell.2020.00461
Subject: Breast progenitor cells; DLK1-DIO3 locus; Epithelial plasticity; MEG3; ncRNAs; Brjóstakrabbamein; DNA-rannsóknir
URI: https://hdl.handle.net/20.500.11815/2318

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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

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.

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