The Implications of the Long Non-Coding RNA NEAT1 in Non-Cancerous Diseases

Abstract

Long non-coding RNAs (lncRNAs) are involved in a variety of biological and cellular processes as well as in physiologic and pathophysiologic events. This review summarizes recent literature about the role of the lncRNA nuclear enriched abundant transcript 1 (NEAT1) in non-cancerous diseases with a special focus on viral infections and neurodegenerative diseases. In contrast to its role as competing endogenous RNA (ceRNA) in carcinogenesis, NEAT1's function in non-cancerous diseases predominantly focuses on paraspeckle-mediated effects on gene expression. This involves processes such as nuclear retention of mRNAs or sequestration of paraspeckle proteins from specific promoters, resulting in transcriptional induction or repression of genes involved in regulating the immune system or neurodegenerative processes. NEAT1 expression is aberrantly-mostly upregulated-in non-cancerous pathological conditions, indicating that it could serve as potential prognostic biomarker. Additional studies are needed to elucidate NEAT1's capability to be a therapeutic target for non-cancerous diseases.

Keywords: NEAT1; long non-coding RNAs; neurodegeneration; paraspeckles; viral diseases.

Figure 1

Nuclear enriched abundant transcript 1 (NEAT1)’s domain architecture and schematic paraspeckle structure. (A) The long isoform of NEAT1 (NEAT1_2) contains three domains which are relevant for binding the paraspeckle-associated proteins 54 kDa nuclear RNA- and DNA-binding protein/non-POU domain-containing octamer-binding protein (p54nrb/NONO; orange), paraspeckle component 1 (PSPC1; yellow), and polypyrimidine tract-binding protein PTB-associated splicing factor/splicing factor proline glutamine rich (PSF/SFPQ; brown). p54nrb/NONO and PSF/SFPQ directly interact with NEAT1’s middle domain, whereas three protein interaction sites near the 5’ and the 3’ end facilitate binding of p54nrb/NONO. All three abovementioned proteins form heterodimers in every possible combination, and thus contribute to the formation of paraspeckles. Only proven interactions of proteins with NEAT1 and each other are shown. (B) Paraspeckles are arranged in a spheroidal, highly ordered structure with NEAT1’s middle domain being located in the center while its 5’ and 3’ termini are at the periphery of the structure. Paraspeckle-associated proteins p54nrb/NONO, PSF/SFPQ, and PSPC1 (as well as other paraspeckle proteins; not shown in figure) are distributed within the structure in consideration of the before established binding domains on NEAT1.

Figure 2

Role of NEAT1 in the regulation of gene expression. NEAT1 influences gene regulation through two predominant functions. On one hand, NEAT1-dependent paraspeckle formation leads to the sequestration of paraspeckle proteins such as PSPC1, PSF/SFPQ, and p54nrb/NONO, therefore limiting their effect on the transcriptional regulation. On the other hand, adenosine-to-inosine (A–I) edited mRNAs are more efficiently bound by formed paraspeckles and in turn more effectively retained in the nucleus, instead of being transported to the cytoplasm.