Dynamic expression of tRNA-derived small RNAs define cellular states.

Srikar Krishna,Srikala Raghavan,Joo Leng Low,Akash Gulyani,Siu Kwan Sze,Dasaradhi Palakodeti,Varsha Tirumalai,Jit Kong Cheong,Jung Eun Park,Ramanuj Dasgupta,Daniel Gr Yim,Vairavan Lakshmanan,Judice Ly Koh,Padubidri Shivaprasad,Michelle Js Lim

doi:10.15252/embr.201947789

Abstract

Transfer RNA (tRNA)‐derived small RNAs (tsRNAs) have recently emerged as important regulators of protein translation and shown to have diverse biological functions. However, the underlying cellular and molecular mechanisms of tsRNA function in the context of dynamic cell‐state transitions remain unclear. Expression analysis of tsRNAs in distinct heterologous cell and tissue models of stem vs. differentiated states revealed a differentiation‐dependent enrichment of 5′‐tsRNAs. We report the identification of a set of 5′‐tsRNAs that is upregulated in differentiating mouse embryonic stem cells (mESCs). Notably, interactome studies with differentially enriched 5′‐tsRNAs revealed a switch in their association with “effector” RNPs and “target” mRNAs in different cell states. We demonstrate that specific 5′‐tsRNAs can preferentially interact with the RNA‐binding protein, Igf2bp1, in the RA‐induced differentiated state. This association influences the transcript stability and thereby translation of the pluripotency‐promoting factor, c‐Myc, thus providing a mechanistic basis for how 5′‐tsRNAs can modulate stem cell states in mESCs. Together our study highlights the role of 5′‐tsRNAs in defining distinct cell states.

Highlights

Transfer RNA-derived small RNAs have recently emerged as important regulators of protein translation and shown to have diverse biological functions
Small RNA-seq in heterologous cell systems reveals that the expression of 50-tRNA-derived small RNAs (tsRNAs) is consistently enriched in differentiated states compared with isogenic stem-like state
Deep sequencing of small RNAs in mouse embryonic stem cells (mESCs) cultured under different conditions including Wnt3a+LIF, LIF alone, and retinoic acid (RA; differentiation) in biological replicates (Fig EV1A) revealed a distinct population of 30–35 nt species (Figs 1A and EV1B) enriched during differentiation

Summary

Introduction

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) have recently emerged as important regulators of protein translation and shown to have diverse biological functions. Expression analysis of tsRNAs in distinct heterologous cell and tissue models of stem vs differentiated states revealed a differentiation-dependent enrichment of 50-tsRNAs. We report the identification of a set of 50tsRNAs that is upregulated in differentiating mouse embryonic stem cells (mESCs). Interactome studies with differentially enriched 50-tsRNAs revealed a switch in their association with “effector” RNPs and “target” mRNAs in different cell states. We demonstrate that specific 50-tsRNAs can preferentially interact with the RNA-binding protein, Igf2bp, in the RA-induced differentiated state. This association influences the transcript stability and thereby translation of the pluripotency-promoting factor, c-Myc, providing a mechanistic basis for how 50-tsRNAs can modulate stem cell states in mESCs. Together our study highlights the role of 50-tsRNAs in defining distinct cell states

Methods

Results

Conclusion