LncRNA EPR controls epithelial proliferation by coordinating Cdkn1a transcription and mRNA decay response to TGF-β

Martina Rossi, Gabriele Bucci, Dario Rizzotto, Domenico Bordo, Matteo J. Marzi, Margherita Puppo, Arielle Flinois, Domenica Spadaro, Sandra Citi, Laura Emionite, Michele Cilli, Francesco Nicassio, Alberto Inga (), Paola Briata () and Roberto Gherzi ()
Additional contact information
Martina Rossi: IRCCS Ospedale Policlinico San Martino
Gabriele Bucci: IRCCS Ospedale San Raffaele
Dario Rizzotto: University of Trento
Domenico Bordo: IRCCS Ospedale Policlinico San Martino
Matteo J. Marzi: Istituto Italiano di Tecnologia (IIT)
Margherita Puppo: IRCCS Ospedale Policlinico San Martino
Arielle Flinois: University of Geneve
Domenica Spadaro: University of Geneve
Sandra Citi: University of Geneve
Laura Emionite: IRCCS Policlinico San Martino
Michele Cilli: IRCCS Policlinico San Martino
Francesco Nicassio: Istituto Italiano di Tecnologia (IIT)
Alberto Inga: University of Trento
Paola Briata: IRCCS Ospedale Policlinico San Martino
Roberto Gherzi: IRCCS Ospedale Policlinico San Martino

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Long noncoding RNAs (lncRNAs) are emerging as regulators of fundamental biological processes. Here we report on the characterization of an intergenic lncRNA expressed in epithelial tissues which we termed EPR (Epithelial cell Program Regulator). EPR is rapidly downregulated by TGF-β and its sustained expression largely reshapes the transcriptome, favors the acquisition of epithelial traits, and reduces cell proliferation in cultured mammary gland cells as well as in an animal model of orthotopic transplantation. EPR generates a small peptide that localizes at epithelial cell junctions but the RNA molecule per se accounts for the vast majority of EPR-induced gene expression changes. Mechanistically, EPR interacts with chromatin and regulates Cdkn1a gene expression by affecting both its transcription and mRNA decay through its association with SMAD3 and the mRNA decay-promoting factor KHSRP, respectively. We propose that EPR enables epithelial cells to control proliferation by modulating waves of gene expression in response to TGF-β.

Date: 2019
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DOI: 10.1038/s41467-019-09754-1

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