The long non-coding RNA PARROT is an upstream regulator of c-Myc and affects proliferation and translation.

Dubravka Vučićević,Sonam Dhamija,David Meierhofer,Maja Gehre,Sascha Sauer,Lennart Friis-Hansen,Ulf Andersson Ørom

doi:10.18632/oncotarget.8985

Abstract

Long non-coding RNAs are important regulators of gene expression and signaling pathways. The expression of long ncRNAs is dysregulated in cancer and other diseases. The identification and characterization of long ncRNAs is often challenging due to their low expression level and localization to chromatin. Here, we identify a functional long ncRNA, PARROT (Proliferation Associated RNA and Regulator Of Translation) transcribed by RNA polymerase II and expressed at a relatively high level in a number of cell lines. The PARROT long ncRNA is associated with proliferation in both transformed and normal cell lines. We characterize the long ncRNA PARROT as an upstream regulator of c-Myc affecting cellular proliferation and translation using RNA sequencing and mass spectrometry following depletion of the long ncRNA. PARROT is repressed during senescence of human mammary epithelial cells and overexpressed in some cancers, suggesting an important association with proliferation through regulation of c-Myc. With this study, we add to the knowledge of cytoplasmic functional long ncRNAs and extent the long ncRNA-Myc regulatory network in transformed and normal cells.

Highlights

The non-coding portion of the mammalian genome is pervasively transcribed resulting in the expression of thousands of mRNAs and long non-coding RNAs [1, 2]
While six long non-coding RNAs (ncRNA) have defined Pol(II) peaks in both cell lines, most (15) are clearly bound by high levels of Pol(II) in one cell line only as shown in Figure 1C, which is recapitulated in the expression level of the long ncRNAs in the respective cell lines, reflecting the tissue-specific properties of long ncRNAs that have mostly been reported for lowly expressed long ncRNAs (Figure 1D)
While the generally low expression level of long ncRNAs is believed to result from post-transcriptional regulation, we asked whether the regulation of a highly expressed long ncRNA is occurring at the promoter level by cloning an upstream region of the annotated transcript into a reporter vector (Figure 1E)

Summary

Introduction

The non-coding portion of the mammalian genome is pervasively transcribed resulting in the expression of thousands of mRNAs and long non-coding RNAs (ncRNA) [1, 2]. Long ncRNAs mediating regulation of tumor-suppressors and oncogenes through various mechanisms have been described [5,6,7]. The long ncRNAs lincRNA-p21 [8]; Pint [9]; PR-lncRNA-1 and PR-lncRNA-10 [5] are regulated by the tumor suppressor p53 and are involved in mediating its effects [6, 10]. The long ncRNA-RB1 is co-expressed with RB1 from a bidirectional promoter and links RB1 transcription to the transcription of another tumor suppressor, Calreticulin, with effects on immunogenic cell death [7]. The long ncRNA ANRIL acts as an oncogene. ANRIL interacts with components of both the PRC1 and www.impactjournals.com/oncotarget

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