Nuclear paraspeckles function in mediating gene regulatory and apoptotic pathways

Abstract

The nucleus is an essential hub for the regulation of gene expression in both spatial and temporal contexts. The complexity required to manage such a feat has resulted in the evolution of multiple sub-structures in the nucleus such as the nucleolus, small cajal bodies and nuclear stress bodies. The paraspeckle is another membraneless structure composed of RNA elements, primarily the long non-coding RNA (lncRNA) Nuclear Enriched Abundant Transcript 1 (NEAT1), associated with RNA binding proteins (RBPs). The paraspeckle is showing signs of being involved in various aspects of gene regulation and its role in many pathologies from cancer to viral infection is beginning to be addressed. Research into paraspeckle-directed gene regulation highlights the increase in the appreciation of the biological significance of non-coding RNA (ncRNA). This review will thus cover the basis of how a structure as large as a paraspeckle forms along with its functions. It will also explore how it effects pathological conditions and can be used in clinical intervention, with special emphasis on the multitude of methods utilised by paraspeckles for apoptotic regulation.

Keywords: Apoptosis; Gene regulation; Microspeckles; Paraspeckle; mRNA retention.

Fig. 1

Schematic of the NEAT1 transcript showing the A domain involved in stabilisation likely through an interaction with a currently unknown RBP preventing NEAT1 degradation. Furthermore there is B domain involved in the formation of the 2 different isomers, this is possibly due to it interacting with HNRNPK which has been shown to prevent polyadenylation of NEAT1 to form the NEAT1_1 transcript thus leading to the production of the NEAT1_2 transcript by repressing Cleavage and polyadenylation specificity factor subunit 6 (CPSF6) [76]. Lastly the C domain which can then be further subdivided into three and is involved in the binding to proteins to build the paraspeckle by recruiting FUS, SPFQ and NONO with the latter 2 forming a coiled coil domain that can bind to other proteins such as RMB14, which like FUS contain prion-like domains, recruiting more proteins to form a large structure aided by the interaction of (SWI/SNF) remodelling complexes.

Fig. 2

Representation of how paraspeckle formation during hypoxia stores F11R transcript to then releases it during normoxic conditions, resulting in an increase in F11R protein, making cells more sensitive to stressful conditions immediately after such an episode.

Fig. 3

A representation of how paraspeckle formation localises the WDR5 protein to prevent it from expressing certain differentiation genes of smooth muscle to allow for easier de-differentiation in case of injury.

Fig. 4

The role of paraspeckles in retaining normal miRNA levels in cells to prevent apoptosis caused by a high concentration of miRNA (dsRNA response) and a low concentration of miRNA (ISG mediated apoptosis).