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Int J Mol Sci. 2018 Feb 16;19(2). pii: E593. doi: 10.3390/ijms19020593.

Luminal lncRNAs Regulation by ERα-Controlled Enhancers in a Ligand-Independent Manner in Breast Cancer Cells.

Author information

1
Center for Molecular Systems Biology, University of Turin, Orbassano, 10043 Turin, Italy. valentina.miano@unito.it.
2
Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, Italy. valentina.miano@unito.it.
3
Center for Molecular Systems Biology, University of Turin, Orbassano, 10043 Turin, Italy. giulio.ferrero@unito.it.
4
Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, Italy. giulio.ferrero@unito.it.
5
Department of Computer Science, University of Turin, 10149 Turin, Italy. giulio.ferrero@unito.it.
6
Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, Italy. rosti@ingm.org.
7
Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, Italy. eleonora.manitta@gmail.com.
8
Center for Molecular Systems Biology, University of Turin, Orbassano, 10043 Turin, Italy. elhasnaouij@gmail.com.
9
Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, Italy. elhasnaouij@gmail.com.
10
Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy. giulia.basile@iigm.it.
11
Center for Molecular Systems Biology, University of Turin, Orbassano, 10043 Turin, Italy. michele.debortoli@unito.it.
12
Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, Italy. michele.debortoli@unito.it.

Abstract

Estrogen receptor-α (ERα) is a ligand-inducible protein which mediates estrogenic hormones signaling and defines the luminal BC phenotype. Recently, we demonstrated that even in absence of ligands ERα (apoERα) binds chromatin sites where it regulates transcription of several protein-coding and lncRNA genes. Noteworthy, apoERα-regulated lncRNAs marginally overlap estrogen-induced transcripts, thus representing a new signature of luminal BC genes. By the analysis of H3K27ac enrichment in hormone-deprived MCF-7 cells, we defined a set of Super Enhancers (SEs) occupied by apoERα, including one mapped in proximity of the DSCAM-AS1 lncRNA gene. This represents a paradigm of apoERα activity since its expression is largely unaffected by estrogenic treatment, despite the fact that E2 increases ERα binding on DSCAM-AS1 promoter. We validated the enrichment of apoERα, p300, GATA3, FoxM1 and CTCF at both DSCAM-AS1 TSS and at its associated SE by ChIP-qPCR. Furthermore, by analyzing MCF-7 ChIA-PET data and by 3C assays, we confirmed long range chromatin interaction between the SE and the DSCAM-AS1 TSS. Interestingly, CTCF and p300 binding showed an enrichment in hormone-depleted medium and in the presence of ERα, elucidating the dynamics of the estrogen-independent regulation of DSCAM-AS1 expression. The analysis of this lncRNA provides a paradigm of transcriptional regulation of a luminal specific apoERα regulated lncRNA.

KEYWORDS:

breast cancer; estrogen receptor; lncRNA; super enhancer

PMID:
29462945
PMCID:
PMC5855815
DOI:
10.3390/ijms19020593
[Indexed for MEDLINE]
Free PMC Article

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