Abstract
The majority of the human genome is made of transposable elements, giving rise to interspaced repeats, including Long INterspersed Element-1s (LINE-1s or L1s). L1s are active human transposable elements involved in genomic diversity and evolution; however, they can also contribute to genomic instability and diseases. L1s require host factors to complete their life cycles, whereas the host has evolved numerous mechanisms to restrict L1-induced mutagenesis. Restriction mechanisms in somatic cells include methylation of the L1 promoter, anti-viral factors and RNA-mediated processes such as small RNAs. microRNAs (miRNAs or miRs) are small non-coding RNAs that post-transcriptionally repress multiple target genes often found in the same cellular pathways. We have recently established that miR-128 functions as a novel restriction factor inhibiting L1 mobilization in somatic cells. We have further demonstrated that miR-128 functions through a dual mechanism; by directly targeting L1 RNA for degradation and indirectly by inhibiting a cellular co-factor which L1 is dependent on to transpose to new genomic locations (TNPO1). Here, we add another piece to the puzzle of the enigmatic L1 lifecycle. We show that miR-128 also inhibits another key cellular factor, hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1), by significantly reducing mRNA and protein levels through direct interaction with the coding sequence (CDS) of hnRNPA1 mRNA. In addition, we demonstrate that repression of hnRNPA1 using hnRNPA1-shRNA significantly decreases de novo L1 retro-transposition and that induced hnRNPA1 expression enhances L1 mobilization. Furthermore, we establish that hnRNPA1 is a functional target of miR-128. Finally, we determine that induced hnRNPA1 expression in miR-128-overexpressing cells can partly rescue the miR-128-induced repression of L1′s ability to transpose to different genomic locations. Thus, we have identified an additional mechanism by which miR-128 represses L1 retro-transposition and mediates genomic stability.
Highlights
Repetitive sequences make up greater than half of the human genome, of which Long INterspaced elements-1 (LINE-1 or L1) account for approximately 17% [1,2,3]
We show that miR-128 significantly decreases hnRNPA1 protein levels, by directly binding to hnRNPA1 mRNA, and that miR-128-induced L1 restriction is partly dependent on targeting hnRNPA1
We have previously demonstrated that miR-128 directly targets L1 RNA and represses de novo retrotransposition and genomic integration in somatic cells [32]
Summary
Repetitive sequences make up greater than half of the human genome, of which Long INterspaced elements-1 (LINE-1 or L1) account for approximately 17% [1,2,3]. In hypomethylated cell populations such as cancer cells or pluripotent stem cells, the L1 promoter is often de-repressed allowing for L1 retrotransposition [22,23,24] Under these conditions, other mechanisms of L1 restriction are crucial, including suppression by DNA and RNA editing proteins, including AID, APOBECs and ADAR [25,26], as well as the microprocessor [27]. We have previously established that miR-128 represses L1 retrotransposons in somatic cells through a dual mechanism, namely by direct targeting of L1 ORF2 mRNA and indirectly through the regulation of a required cellular co-factor, Transportin 1 (TNPO1) [32,33]. We have discovered another key player in the L1 life cycle, which is subjected to miR-128 regulation
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