Integrated genomic analysis reveals regulatory pathways and dynamic landscapes of the tRNA transcriptome

Zefang Sun,Jia Tan,Xing Yu,Ming Xie,Feilong Wu,Qiyao Peng,Yide Yang,Zuping He,Mingqing Zhou,Yangyang Dong,Junhua Zhou,Minqiong Zhao,Quanyuan He,Xianghua Liu,Shanru Zuo,Quanze He,Xueguang Li

doi:10.1038/s41598-021-83469-6

Abstract

tRNAs and tRNA-derived RNA fragments (tRFs) play various roles in many cellular processes outside of protein synthesis. However, comprehensive investigations of tRNA/tRF regulation are rare. In this study, we used new algorithms to extensively analyze the publicly available data from 1332 ChIP-Seq and 42 small-RNA-Seq experiments in human cell lines and tissues to investigate the transcriptional and posttranscriptional regulatory mechanisms of tRNAs. We found that histone acetylation, cAMP, and pluripotency pathways play important roles in the regulation of the tRNA gene transcription in a cell-specific manner. Analysis of RNA-Seq data identified 950 high-confidence tRFs, and the results suggested that tRNA pools are dramatically distinct across the samples in terms of expression profiles and tRF composition. The mismatch analysis identified new potential modification sites and specific modification patterns in tRNA families. The results also show that RNA library preparation technologies have a considerable impact on tRNA profiling and need to be optimized in the future.

Highlights

TRNAs and tRNA-derived RNA fragments play various roles in many cellular processes outside of protein synthesis
We identified 85, 76 and 25 proteins bound to the tRNA genes in HepG2, K562, and H1-ES cells, respectively
We extensively investigated the regulatory mechanisms and landscapes of tRNA using 1332 ChipSeq datasets and 36 small-RNA-Seq datasets from human cell lines and tissues and found that tRNA genes are regulated by distinct transcriptional regulators, including histone acetylation, cAMP, and pluripotency pathways

Summary

Introduction

TRNAs and tRNA-derived RNA fragments (tRFs) play various roles in many cellular processes outside of protein synthesis. We used new algorithms to extensively analyze the publicly available data from 1332 ChIP-Seq and 42 small-RNA-Seq experiments in human cell lines and tissues to investigate the transcriptional and posttranscriptional regulatory mechanisms of tRNAs. We found that histone acetylation, cAMP, and pluripotency pathways play important roles in the regulation of the tRNA gene transcription in a cell-specific manner. Recent evidence suggests that tRNAs perform additional functions, such as acting as signaling molecules in numerous metabolic and cellular processes in both prokaryotes and eukaryotes, and are implicated in the translational regulation of mRNA expression, animal development, and diseases[1,2,3]. Next-generation ChIP-Seq and RNA-Seq technologies are powerful tools used to decode the mechanisms of tRNA regulation and expression profiles in the cells. The Iso-tRNA-CP algorithm was designed to evaluate the relative expression levels of the tRNA genes based on their proportional transcript contribution to a corresponding isodecoder set to reduce the effects of sequencing b ias[17]

Methods

Results

Discussion

Conclusion