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Genome Biol. 2017 Oct 6;18(1):189. doi: 10.1186/s13059-017-1321-0.

The nuclear receptor ERβ engages AGO2 in regulation of gene transcription, RNA splicing and RISC loading.

Author information

1
Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, via S. Allende, 1, 84081, Baronissi, SA, Italy.
2
Genomix4Life srl, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, Baronissi, SA, Italy.
3
IRCCS SDN, Napoli, Italy.
4
Department of Cardiothoracic and Respiratory Sciences, University of Campania'L. Vanvitelli', Naples, Italy.
5
Institute of Biomedical Technologies, National Research Council, Segregate, MI, Italy.
6
Department of Science and Technology, University of Sannio, Benevento, Italy.
7
IRGS Biogem, Ariano Irpino, AV, Italy.
8
Department of Immunology, Institute of Clinical Medicine, University of Oslo and Rikshospitalet Oslo, Oslo, Norway.
9
Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, via S. Allende, 1, 84081, Baronissi, SA, Italy. gnassa@unisa.it.
10
Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, via S. Allende, 1, 84081, Baronissi, SA, Italy. aweisz@unisa.it.

Abstract

BACKGROUND:

The RNA-binding protein Argonaute 2 (AGO2) is a key effector of RNA-silencing pathways It exerts a pivotal role in microRNA maturation and activity and can modulate chromatin remodeling, transcriptional gene regulation and RNA splicing. Estrogen receptor beta (ERβ) is endowed with oncosuppressive activities, antagonizing hormone-induced carcinogenesis and inhibiting growth and oncogenic functions in luminal-like breast cancers (BCs), where its expression correlates with a better prognosis of the disease.

RESULTS:

Applying interaction proteomics coupled to mass spectrometry to characterize nuclear factors cooperating with ERβ in gene regulation, we identify AGO2 as a novel partner of ERβ in human BC cells. ERβ-AGO2 association was confirmed in vitro and in vivo in both the nucleus and cytoplasm and is shown to be RNA-mediated. ChIP-Seq demonstrates AGO2 association with a large number of ERβ binding sites, and total and nascent RNA-Seq in ERβ + vs ERβ - cells, and before and after AGO2 knock-down in ERβ + cells, reveals a widespread involvement of this factor in ERβ-mediated regulation of gene transcription rate and RNA splicing. Moreover, isolation and sequencing by RIP-Seq of ERβ-associated long and small RNAs in the cytoplasm suggests involvement of the nuclear receptor in RISC loading, indicating that it may also be able to directly control mRNA translation efficiency and stability.

CONCLUSIONS:

These results demonstrate that AGO2 can act as a pleiotropic functional partner of ERβ, indicating that both factors are endowed with multiple roles in the control of key cellular functions.

KEYWORDS:

Argonaute 2; Breast cancer; Estrogen receptor beta; Interaction proteomics; RNA splicing; Transcriptional regulation

PMID:
29017520
PMCID:
PMC5634881
DOI:
10.1186/s13059-017-1321-0
[Indexed for MEDLINE]
Free PMC Article

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