tRNA-Derived Small RNAs: Novel Epigenetic Regulators

Abstract

An epigenetic change is a heritable genetic alteration that does not involve any nucleotide changes. While the methylation of specific DNA regions such as CpG islands or histone modifications, including acetylation or methylation, have been investigated in detail, the role of small RNAs in epigenetic regulation is largely unknown. Among the many types of small RNAs, tRNA-derived small RNAs (tsRNAs) represent a class of noncoding small RNAs with multiple roles in diverse physiological processes, including neovascularization, sperm maturation, immune modulation, and stress response. Regarding these roles, several pioneering studies have revealed that dysregulated tsRNAs are associated with human diseases, such as systemic lupus, neurological disorder, metabolic disorder, and cancer. Moreover, recent findings suggest that tsRNAs regulate the expression of critical genes linked with these diseases by a variety of mechanisms, including epigenetic regulation. In this review, we will describe different classes of tsRNAs based on their biogenesis and will focus on their role in epigenetic regulation.

Keywords: cancer; epigenetics; tRF; tRNA fragment; tRNA-derived small RNA; tiRNA; transfer RNA; tsRNA.

Figure 1

Classification and biogenesis of tRNA-derived small RNAs. More than 6 types of tsRNAs have been classified based on the site at which precursor tRNAs are cleaved. tsRNAs are formed by the processing of their precursors (i.e., mature tRNAs or pre-tRNAs). Cleavage sites are indicated by red arrowheads. Variations in length observed in 5′ tsRNAs (Type I tsRNAs) are indicated by a red dotted line. tRNA halves are primarily processed by angiogenin and Dicer proteins (the name of the minor processing enzyme is shown in gray). The major processing enzymes for other tsRNAs generated from mature tRNAs have not been determined.

Figure 2

PIWI-dependent epigenetic regulation and function of tRNA-derived small RNAs: (A) Regulation of RNA processing in the nucleus. The Twi12-3′ tsRNA complex plays a role in cell proliferation. It also plays a role in the stabilization and nucleolar localization of Xrn2, a 5′ monophosphate-dependent nuclear exonuclease that is required for ribosomal RNA processing in the nucleus. (B) Histone modification in immune cells. IL-4 affects tRNA(Glu) expression; consequently, it inhibits the expression of the tRNA(Glu)-derived piRNA (td-piR(Glu)) precursor. td-piR(Glu) associates with PIWIL4 and recruits H3K9 methyltransferases (SETDB1 and SUV39H1) and heterochromatin protein 1β (HP1β) to the CD1A promoter region, thereby facilitating H3K9 methylation. Hence, the transcription of CD1A is inhibited.

Figure 3

PIWI-independent epigenetic regulation and function of tRNA-derived small RNAs (A) Regulation of transposon activity. Intact mature tRNAs play a role as primers during the reverse transcription of ERVs; 3′ tsRNAs (18-nt long; red line) interrupt this process by competing for the primer binding site (PBS), whereas 22 nt long 3′ tsRNAs induce post-transcriptional silencing of retroviral proteins by targeting their mRNA. (B) Regulation of chromatin accessibility; 5′tRF-Gly-GCC (tRF-GG) directly binds to heterogeneous nuclear ribonucleoproteins F and H (hnRNP F/H), thereby forming a complex. This complex is required for the biogenesis of a normal Cajal body. Further, U7 snRNA is required for histone expression by base pairing with the histone downstream element (HDE). Consequently, elevated histone levels affect the expression of MERVL-associated genes via altering the chromatin status (euchromatin to heterochromatin). (C) Regulation of adipogenesis. Increased levels of tRF^GluTTC induce the expression of several cell cycle regulatory factors, such as Cyclin D1, CDK4, and Cyclin E, thereby promoting preadipocyte proliferation, while inhibiting 3T3-L1 preadipocyte differentiation. tRF^GluTTC–mediated inhibition results in reduced expression of fatty acid synthesis-related genes and a decrease in triglyceride content and lipid accumulation. Finally, increased levels of tRF^GluTTC inhibit result in the inhibition of mRNA translation of Krüppel-like factor (KLF) family members through hybridization to KLF 3′ UTR.