Retrotransposons as regulators of gene expression

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Science  12 Feb 2016:
Vol. 351, Issue 6274, aac7247
DOI: 10.1126/science.aac7247


  • Some of the steps in the expression of mammalian genes that can be affected by cis- or trans-acting LINEs or SINEs.

    LINE and SINE genomic insertions can regulate gene expression by altering transcription and/or chromatin structure. When embedded in the transcripts of RNA polymerase II (Pol II)–transcribed genes, SINEs can influence nuclear pre-mRNA splicing, nuclear mRNA retention in paraspeckles, cytoplasmic mRNA stability, or cytoplasmic mRNA translation.​ ARE-BP, AU-rich element–binding protein.

  • 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 p54nrb, which is relieved by Staufen binding or by CARM1-mediated methylation of p54nrb. 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.


  • Table 1. Some human diseases linked to LINE and SINE insertions.

    The extensive role of LINEs and SINEs in the regulation of human gene expression suggests that they contribute to disease in as yet undiscovered ways.

    Effect of LINE or SINE insertionPossible mechanism(s) of pathogenesisExamples of associated diseasesReference
    Genomic deletions and rearrangementsLINE/SINE-mediated homologous recombination: DNA sequence loss; genomic instabilityProstate cancer, pyruvate dehydrogenase complex deficiency, leukemia, Alport syndrome, breast cancer (83)
    Hereditary nonpolyposis colorectal cancer, Von Hippel–Lindau disease (86)
    Disruption of protein‐coding sequencesAberrant protein production; nonsense‐mediated mRNA decay (NMD)Hemophilia B, breast cancer, colon cancer, neurofibromatosis type 1 (83)
    Altered DNA methylationIncreased expression of LINE and SINE RNAEarly event in many cancers (86)
    Altered pre‐mRNA splicingAberrant protein production; NMDFukuyama-type congenital muscular dystrophy, neurofibromatosis type 1, hemophilia A (83)
    Neurofibromatosis type 1, hemophilia A, breast cancer, Coffin‐Lowry syndrome (84)
    Altered 3′-end formationPremature transcription termination; altered protein production; NMD; altered mRNA stability, localization, or translatabilityX‐linked retinitis pigmentosa (83)
    Altered mRNA stabilityReduced protein production; altered temporal and/or spatial gene expressionX-linked dilated cardiomyopathy (83)
    Hemophilia A, hereditary nonpolyposis colorectal cancer, hyper–immunoglobulin M syndrome (84)
    Sites of A-to‐I editingLoss of ADAR editing of target sites, possibly at Alu elementsAmyotrophic lateral sclerosis (ALS), astrocytoma, metastatic melanoma, Aicardi-Goutières syndrome, hepatocellular carcinoma (100)

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