Posttranscriptional gene regulation by long noncoding RNA

Abstract

Eukaryotic cells transcribe a vast number of noncoding RNA species. Among them, long noncoding RNAs (lncRNAs) have been widely implicated in the regulation of gene transcription. However, examples of posttranscriptional gene regulation by lncRNAs are emerging. Through extended base-pairing, lncRNAs can stabilize or promote the translation of target mRNAs, while partial base-pairing facilitates mRNA decay or inhibits target mRNA translation. In the absence of complementarity, lncRNAs can suppress precursor mRNA splicing and translation by acting as decoys of RNA-binding proteins or microRNAs and can compete for microRNA-mediated inhibition leading to increased expression of the mRNA. Through these regulatory mechanisms, lncRNAs can elicit differentiation, proliferation, and cytoprotective programs, underscoring the rising recognition of lncRNA roles in human disease. In this review, we summarize the mechanisms of posttranscriptional gene regulation by lncRNAs identified until now.

Keywords: BACE1; PABP; RNA-binding protein; lincRNA; lncRNA; long noncoding RNA; mRNA turnover; poly(A)-binding protein; pre-mRNA; precursor mRNA; small nucleolar lncRNA; sno-lncRNA; translational regulation; β amyloid-cleaving enzyme 1.

Figure 1

Levels of post-transcriptional gene regulation by lncRNAs. The major post-transcriptional processes influenced by lncRNAs are indicated in black boxes. (1) Splicing of pre-mRNAs, which is modulated by lncRNAs that compete for binding for splicing regulatory proteins (e.g., SR, Fox). (2) Protection from mRNA decay, as exemplified by lncRNA BACE1-AS, which forms a hybrid and hence prevents the decay of BACE1 mRNA. (3) Acceleration of mRNA decay, as reported for ½-sbsRNAs, which function jointly with Staufen 1 to promote the decay of Alu-containing mRNAs. (4) Repression of mRNA translation, as demonstrated for lincRNA-p21 via interaction with partially complementary mRNAs and recruitment of translation repressors Rck and Fmrp. (5) Activation of mRNA translation, as illustrated by the interaction of AS Uchl1 via a SINEB2 sequence and a segment fully complementary with the 5’ end of Uchl1 mRNA; this association helps to recruit ribosomes to Uchl1 mRNA and enhances its translation. (6) Functional association with microRNAs, as shown for linc-MD1, which ‘sponges’ microRNAs, for H19, which hosts microRNAs, and for BACE1-AS, which promotes BACE1 mRNA translation by competing with a microRNA. See text for further details.