Abstract

There is growing evidence that peptides encoded by small open-reading frames (sORF or smORF) can fulfill various cellular functions and define a novel class regulatory molecules. To which extend transcripts encoding only smORF peptides compare with canonical protein-coding genes, yet remain poorly understood. In particular, little is known on whether and how smORF-encoding RNAs might need tightly regulated expression within a given tissue, at a given time during development. We addressed these questions through the analysis of Drosophila polished rice (pri, a.k.a. tarsal less or mille pattes), which encodes four smORF peptides (11–32 amino acids in length) required at several stages of development. Previous work has shown that the expression of pri during epidermal development is regulated in the response to ecdysone, the major steroid hormone in insects. Here, we show that pri transcription is strongly upregulated by ecdysone across a large panel of cell types, suggesting that pri is a core component of ecdysone response. Although pri is produced as an intron-less short transcript (1.5 kb), genetic assays reveal that the developmental functions of pri require an unexpectedly large array of enhancers (spanning over 50 kb), driving a variety of spatiotemporal patterns of pri expression across developing tissues. Furthermore, we found that separate pri enhancers are directly activated by the ecdysone nuclear receptor (EcR) and display distinct regulatory modes between developmental tissues and/or stages. Alike major developmental genes, the expression of pri in a given tissue often involves several enhancers driving apparently redundant (or shadow) expression, while individual pri enhancers can harbor pleiotropic functions across tissues. Taken together, these data reveal the broad role of Pri smORF peptides in ecdysone signaling and show that the cis-regulatory architecture of the pri gene contributes to shape distinct spatial and temporal patterns of ecdysone response throughout development.

Highlights

  • Recent advances in functional genomics indicate that apparently non-coding RNAs often encode smORF peptides (Andrews and Rothnagel, 2014; Pauli et al, 2015; Pueyo et al, 2016) and Polished rice represents a paradigm of this emerging field (Andrews and Rothnagel, 2014; Zanet et al, 2016)

  • ecdysone nuclear receptor (EcR) activates the expression of early-acting TFs (Br, Eip75B), EcR needs the activity of early TFs to trigger the expression of additional genes (Hr4, Hr3) mediating the response to ecdysone. (B) Heat map showing differential expression of genes (Log2FC) encoding ecdysone-response TFs (Hr4, Eip75B, Eip74EF, Br, Blimp-1, or ftz-f1) and pri in 41 Drosophila cell lines after vs. before 5 h of ecdysone treatment

  • We found that pri expression involves a wide array of enhancers, some of them being likely directly controlled by the ecdysone nuclear receptor EcR (Figure 8)

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Summary

Introduction

Recent advances in functional genomics indicate that apparently non-coding RNAs often encode smORF peptides (Andrews and Rothnagel, 2014; Pauli et al, 2015; Pueyo et al, 2016) and Polished rice (pri) represents a paradigm of this emerging field (Andrews and Rothnagel, 2014; Zanet et al, 2016). The complete loss of pri function yet results in embryonic lethality; pri mutants display severe defects of the tracheal respiratory system (Kondo et al, 2007, 2010; Ozturk-Colak et al, 2016). Another prominent phenotype of pri embryos is a deep alteration of epidermal development, including the absence of trichomes (Galindo et al, 2007; Kondo et al, 2007). The program of trichome differentiation is set up with the accumulation of the Svb repressor and kept on hold until pri is expressed

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