Retrotransposons as regulators of gene expression

Abstract

Transposable elements (TEs) are both a boon and a bane to eukaryotic organisms, depending on where they integrate into the genome and how their sequences function once integrated. We focus on two types of TEs: long interspersed elements (LINEs) and short interspersed elements (SINEs). LINEs and SINEs are retrotransposons; that is, they transpose via an RNA intermediate. We discuss how LINEs and SINEs have expanded in eukaryotic genomes and contribute to genome evolution. An emerging body of evidence indicates that LINEs and SINEs function to regulate gene expression by affecting chromatin structure, gene transcription, pre-mRNA processing, or aspects of mRNA metabolism. We also describe how adenosine-to-inosine editing influences SINE function and how ongoing retrotransposition is countered by the body's defense mechanisms.

Fig. 1. LINE and SINE transposition

(A) Copy step of a LINE: L1 gene transcription by Pol II followed by L1 RNA translation. (B) Paste steps of L1 and Alu element transposition using the endonuclease (ENDO) and reverse transcriptase (RT) activities of ORF2p. (C) Copy step of a SINE: Alu element transcription by Pol III. (D) Intrachromosomal recombination between related LINEs or SINEs resulting in genomic deletion. (E) Interchromosomal recombination between related LINEs or SINEs resulting in genomic rearrangements.

Fig. 2. LINE- and SINE-mediated gene regulation

(A) SINEs (and LINEs) can promote or inhibit the transcription of nearby genes. TSS, transcription start site; TF, transcription factor. (B) Upon heat shock, increased expression of Alu and B2 RNAs inhibits Pol II. (C) SINEs contain potential splice sites (ss) that, if used, can lead to mRNAs with intronic sequences. (D) SINEs (in particular, Alu elements) can contain a polyadenylation signal (PAS).

Fig. 3. Effects on mRNA stability by SINE insertions

(A) AU-rich element–binding proteins (ARE-BPs) may bind a 3′UTR Alu element–derived ARE and either stabilize or destabilize the mRNA. (B) Alu element–derived microRNA-binding sites within an mRNA can promote mRNA decay and/or inhibit mRNA translation. (C) Intermolecular base pairing via partially complementary SINEs can create Staufen-binding sites that trigger Staufen-mediated mRNA decay.

Fig. 4. 3′UTR IRAlus regulate mRNA localization and translation

(A) During cellular interphase, 3′UTR IRAlus localize many newly synthesized mRNAs to nuclear paraspeckles by binding p54^nrb, which is relieved by Staufen binding or by CARM1-mediated methylation of p54^nrb. In the cytoplasm, 3′UTR IRAlus can inhibit mRNA translation in cis and in trans by binding PKR, and this inhibition is relieved by STAU1 binding. (B) During mitosis, breakdown of the nuclear envelope allows mixing of nuclear-retained 3′UTR IRAlus and cytoplasmic PKR, resulting in PKR binding to 3′UTR IRAlus and PKR-mediated phosphorylation of JNK.

Fig. 5. The roles of A-to-I editing of IRAlus

(A) Edited intronic IRAlus can create a new splice site. (B) Editing in IRAlus might destabilize their dsRNA structure and reduce dsRBP binding.