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De novo and inherited mutations of X-chromosome cell adhesionmolecule protocadherin 19 (PCDH19) cause frequent, highly variable epilepsy, autism, cognitive decline and behavioural problems syndrome. Intriguingly, hemizygous nullmales are not affected while heterozygous females are, contradicting established X-chromosome inheritance. The disease mechanism is not known. Cellular mosaicism is the likely driver. We have identified p54nrb/NONO, amultifunctional nuclear paraspeckle protein with known roles in nuclear hormone receptor gene regulation, as a PCDH19 protein interacting partner. Using breast cancer cells we show that PCDH19-NONO complex is a positive co-regulator of ERa-mediated gene expression. Expression of mutant PCDH19 affects at least a subset of known ERα-regulated genes. These data are consistent with our findings that genes regulated by nuclear hormone receptors and those involved in themetabolism of neurosteroids in particular are dysregulated in PCDH19-epilepsy girls and affected mosaicmales. Overall we define and characterize a novelmechanism of gene regulation driven by PCDH19, which is mediated by paraspeckle constituent NONO and is ERα-dependent. This PCDH19-NONO-ERa axis is of relevance not only to PCDH19-epilepsy and its comorbidities but likely also to ERα and generally nuclear hormone receptor-associated cancers. Refereed/Peer-reviewed

Members of the Drosophila behavior/human splicing protein family, including splicing factor proline/glutamine rich (SFPQ), non-POU domain-containing octamer-binding protein (NONO), and paraspeckle protein component 1 (PSPC1), are abundantly expressed in testicular Sertoli cells (SCs), but their roles remain obscure. Here, we show that treatment with mono-(2-ethylhexyl) phthalate (MEHP), a well-known SC toxicant, selectively stimulates the expression levels of NONO and PSPC1. Simultaneous inhibition of NONO and PSPC1 expression in SCs enhances MEHP-induced oxidative stress and potentiates SC death. Mechanistically, NONO and PSPC1 transcriptionally activate aldehyde dehydrogenase 1 (Aldh1a1), by synergistically binding to the distinct CCGGAGTC sequence in the Aldh1a1 promoter. Together, the NONO/PSPC1-ALDH1A1 cascade may serve as an indispensable defense mechanism against MEHP insult in SCs.

A highly orchestrated gene expression program establishes the properties that define mature adipocytes, but the contribution of posttranscriptional factors to the adipocyte phenotype is poorly understood. Here we have shown that the RNA-binding protein PSPC1, a component of the paraspeckle complex, promotes adipogenesis in vitro and is important for mature adipocyte function in vivo. Cross-linking and immunoprecipitation followed by RNA sequencing revealed that PSPC1 binds to intronic and 3'-untranslated regions of a number of adipocyte RNAs, including the RNA encoding the transcriptional regulator EBF1. Purification of the paraspeckle complex from adipocytes further showed that PSPC1 associates with the RNA export factor DDX3X in a differentiation-dependent manner. Remarkably, PSPC1 relocates from the nucleus to the cytoplasm during differentiation, coinciding with enhanced export of adipogenic RNAs. Mice lacking PSPC1 in fat displayed reduced lipid storage and adipose tissue mass and were resistant to diet-induced obesity and insulin resistance due to a compensatory increase in energy expenditure. These findings highlight a role for PSPC1-dependent RNA maturation in the posttranscriptional control of adipose development and function.

Nuclear paraspeckle assembly transcript 1 (NEAT1) is the crucial structural platform of paraspeckles, which is one type of nuclear bodies. As a stress-induced lncRNA, the expression of NEAT1 increases in response to viral infection, but little is known about the role of NEAT1 or paraspeckles in the replication of herpes simplex virus-1 (HSV-1). Here, we demonstrate that HSV-1 infection increases NEAT1 expression and paraspeckle formation in a STAT3-dependent manner. NEAT1 and other paraspeckle protein components, P54nrb and PSPC1, can associate with HSV-1 genomic DNA. By binding with STAT3, PSPC1 is required for the recruitment of STAT3 to paraspeckles and facilitates the interaction between STAT3 and viral gene promoters, finally increasing viral gene expression and viral replication. Furthermore, thermosensitive gel containing NEAT1 siRNA or STAT3 siRNA effectively healed the skin lesions caused by HSV-1 infection in mice. Our results provide insight into the roles of lncRNAs in the epigenetic control of viral genes and into the function of paraspeckles. Electronic supplementary material The online version of this article (doi:10.1007/s00018-016-2398-4) contains supplementary material, which is available to authorized users.

Nuclear paraspeckle assembly transcript 1 (NEAT1) is a long noncoding RNA that functions as an essential framework of subnuclear paraspeckle bodies. Of the two isoforms (NEAT1_1 and NEAT1_2) produced by alternative 3'-end RNA processing, the longer isoform, NEAT1_2, plays a crucial role in paraspeckle formation. Here, we demonstrate that the 3'-end processing and stability of NEAT1 RNAs are regulated by arsenic resistance protein 2 (ARS2), a factor interacting with the cap-binding complex (CBC) that binds to the m7G cap structure of RNA polymerase II transcripts. The knockdown of ARS2 inhibited the association between NEAT1 and mammalian cleavage factor I (CFIm), which produces the shorter isoform, NEAT1_1. Furthermore, the knockdown of ARS2 led to the preferential stabilization of NEAT1_2. As a result, NEAT1_2 RNA levels were markedly elevated in ARS2 knockdown cells, leading to an increase in the number of paraspeckles. These results reveal a suppressive role for ARS2 in NEAT1_2 expression and the subsequent formation of paraspeckles.

Splicing factor proline/glutamine-rich (SFPQ) is an essential RNA-binding protein that is implicated in many aspects of nuclear function. The structures of SFPQ and two paralogs, non-POU domain-containing octamer-binding protein and paraspeckle component 1, from theDrosophilabehavior human splicing protein family have previously been characterized. The unusual arrangement of the four domains, two RNA-recognition motifs (RRMs), a conserved region termed the NonA/paraspeckle (NOPS) domain and a C-terminal coiled coil, in the intertwined dimer provides a potentially unique RNA-binding surface. However, the molecular details of how the four RRMs in the dimeric SFPQ interact with RNA remain to be characterized. Here, a new crystal structure of the dimerization domain of human SFPQ in theC-centered orthorhombic space groupC2221with one monomer in the asymmetric unit is presented. Comparison of the new crystal structure with the previously reported structure of SFPQ and analysis of the solution small-angle X-scattering data revealed subtle domain movements in the dimerization domain of SFPQ, supporting the concept of multiple conformations of SFPQ in equilibrium in solution. The domain movement of RRM1, in particular, may reflect the complexity of the RNA substrates of SFPQ. Taken together, the crystal and solution structure analyses provide a molecular basis for further investigation into the plasticity of nucleic acid binding by SFPQ in the absence of the structure in complex with its cognate RNA-binding partners.

Increasing evidence has suggested that long non‑coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has critical roles in multiple biological processes; however, few studies have reported on its function in heart disease. The present study indicated that NEAT1 expression is markedly downregulated in cardiomyocytes following ischemia/reperfusion injury in vivo and hydrogen peroxide treatment in vitro. Further experiments suggested that ectopic overexpression of NEAT1 suppresses cardiomyocyte apoptosis induced by hydrogen peroxide, as assessed by TUNEL assay and flow cytometry. In addition, using a dual‑luciferase reporter assay, NEAT1 was demonstrated to directly interact with microRNA (miR)‑125a‑5p and overexpression of miR‑125a‑5p efficiently reversed the stimulatory effect of NEAT1 on B‑cell lymphoma‑2‑like 12 (BCL2L12) expression. Furthermore, the results indicated that NEAT1 inhibits cardiomyocyte apoptosis via regulating the expression of BCL2L12, which appeared to be mediated via miR‑125a‑5p. In conclusion, the present study suggested that NEAT1 functions as a miR sponge to inhibit cardiomyocyte apoptosis and may be a novel therapeutic target for cardiomyocyte apoptosis‑associated heart diseases.

Long noncoding RNAs (lncRNAs) are extremely diverse and have various significant physiological functions. lncRNAs generally associate with specific sets of RNA-binding proteins (RBPs) to form functional ribonucleoprotein (RNP) complexes. NEAT1 is a highly abundant lncRNA in the mammalian cell nucleus that associates with specific RBPs to form NEAT1 RNPs. Intriguingly, cellular NEAT1 RNPs are extraordinarily large and can be detected using an optical microscope. These gigantic RNPs, so-called paraspeckles, are a type of membraneless nuclear body. Paraspeckles contain approximately 50 NEAT1 RNA molecules together with characteristic RBPs possessing aggregation-prone prion-like domains. Paraspeckle formation proceeds on the nascent NEAT1 transcript in conjunction with NEAT1 biogenesis, which exhibits various features that differ from those exhibited by mRNA biogenesis, including a lack of introns, noncanonical 3 ' end formation, and nuclear retention. These unique features may be required for the mechanism of paraspeckle formation. NEAT1 possesses three distinct RNA domains (A, B, and C), which function in stabilization (A), isoform switching (B), and paraspeckle assembly (C). In particular, the central C domain contains smaller subdomains that are high-affinity binding sites for the essential paraspeckle proteins (NONO and SFPQ) that subsequently polymerize along NEAT1. Subsequent recruitment of additional essential PSPs (FUS and RBM14) induces liquid-liquid phase separation to build a massive paraspeckle structure. Thus, the molecular anatomy of the NEAT1 arcRNA provides an ideal model to understand how lncRNAs form the functional RNP machinery. This article is characterized under: RNA Export and Localization > Nuclear Export/Import RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications

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.

Aside from their roles in the cytoplasm, RNA-interference components have been reported to localize also in the nucleus of human cells. In particular, AGO1 associates with active chromatin and appears to influence global gene expression. However, the mechanistic aspects remain elusive. Here, we identify AGO1 as a paraspeckle component that in combination with the NEAT1 lncRNA maintains 3D genome architecture. We demonstrate that AGO1 interacts with NEAT1 lncRNA and its depletion affects NEAT1 expression and the formation of paraspeckles. By Hi-C analysis in AGO1 knockdown cells, we observed global changes in chromatin organization, including TADs configuration, and A/B compartment mixing. Consistently, distinct groups of genes located within the differential interacting loci showed altered expression upon AGO1 depletion. NEAT1 knockout cells displayed similar changes in TADs and higher-order A/B compartmentalization. We propose that AGO1 in association with NEAT1 lncRNA can act as a scaffold that bridges chromatin and nuclear bodies to regulate genome organization and gene expression in human cells.

The GGGGCC (G(4)C(2)) repeat expansion mutation in the C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Transcription of the repeat and formation of nuclear RNA foci, which sequester specific RNA-binding proteins, is one of the possible pathological mechanisms. Here, we show that (G(4)C(2))(n) repeat RNA predominantly associates with essential paraspeckle proteins SFPQ, NONO, RBM14, FUS and hnRNPH and colocalizes with known paraspeckle-associated RNA hLinc-p21. As formation of paraspeckles in motor neurons has been associated with early phases of ALS, we investigated the extent of similarity between paraspeckles and (G(4)C(2))(n) RNA foci. Overexpression of (G(4)C(2))(72) RNA results in their increased number and colocalization with SFPQ-stained nuclear bodies. These paraspeckle-like (G(4)C(2))(72) RNA foci form independently of the known paraspeckle scaffold, the long non-coding RNA NEAT1. Moreover, the knockdown of SFPQ protein in C9ORF72 expansion mutation-positive fibroblasts significantly reduces the number of (G(4)C(2))(n) RNA foci. In conclusion, (G(4)C(2))(n) RNA foci have characteristics of paraspeckles, which suggests that both RNA foci and paraspeckles play roles in FTD and ALS, and implies approaches for regulation of their formation.

The encephalomyocarditis virus (EMCV) is a single-stranded RNA virus that induces sudden death, diabetes, myocarditis and nervous disorders in non-human primates. The rapid development of xenografts such as heart transplantation from pig to human raises the issue of EMCV safety in human cells. SFPQ, a proline and glutamine rich splicing factor that participates in diverse molecular functions including paraspeckle formation, microRNA synthesis and transcription regulation, is known to regulate host innate immune response to viruses. However, the role of SFPQ in EMCV infection remains unclear. Here we reported that the SFPQ was essential for EMCV replication. Depletion of SFPQ impaired EMCV production, while forced expression of SFPQ promoted viral replication. Mechanistically, loss of SFPQ affected the transcription profile of host mitochondria pathway related genes. In addition, cellular SFPQ was exploited by EMCV and accumulated in cytoplasm and it interacted with eukaryotic initiation factors and ribosomal proteins to facilitate internal ribosome entry site (IRES)-dependent translation of EMCV protein. Altogether, our work discovered host SFPQ as a new target to inhibit EMCV replication and infection.

The accumulation of intracellular β-amyloid peptide (Aβ) is important pathological characteristic of Alzheimer’s disease (AD). However, the exact underlying molecular mechanism remains to be elucidated. Here, we reported that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), a long n on-coding RNA, exhibits repressed expression in the early stage of AD and its down-regulation declines neuroglial cell mediating Aβ clearance via inhibiting expression of endocytosis-related genes. We find that NEAT1 is associated with P300/CBP complex and its inhibition affects H3K27 acetylation (H3K27Ac) and H3K27 crotonylation (H3K27Cro) located nearby to the transcription start site of many genes, including endocytosis-related genes. Interestingly, NEAT1 inhibition down-regulates H3K27Ac but up-regulates H3K27Cro through repression of acetyl-CoA generation. NEAT1 also mediates the binding between STAT3 and H3K27Ac but not H3K27Cro. Therefore, the decrease of H3K27Ac and/or the increase of H3K27Cro declines expression of multiple related genes. Collectively, this study first reveals the different roles of H3K27Ac and H3K27Cro in regulation of gene expression and provides the insight of the epigenetic regulatory mechanism of NEAT1 in gene expression and AD pathology. Electronic supplementary material The online version of this article (10.1007/s00018-019-03074-9) contains supplementary material, which is available to authorized users.

Nuclear Enriched Abundant Transcript 1 (NEAT1) is a long non-coding RNA (lncRNA) which is a crucial structural constituent of paraspeckles and has an indispensable role in the formation of paraspeckle. Paraspeckles as nuclear sub-structures are placed in the nucleus interchromatin area and participate in the regulation of gene expression through various mechanisms including mRNA retaining, mRNA breakage, A-to-I editing and protein seizing. Several studies have noted participation of NEAT1 in the pathogenesis of human malignancies. Notably, studies have revealed distinct roles for this lncRNA in the pathogenesis of cancer. While most cancerous tissues exhibit up-regulation of NEAT1, expression of this lncRNA has been down-regulated in leukemia and multiple myeloma. Such distinctive pattern of expression implies diverse roles for this lncRNA in solid tumor versus hematological malignancies. Critical roles of NEAT1 in regulation of apoptosis, cell growth and proliferation, invasion and metastasis in several tissues indicate that this lncRNA might be a therapeutic target in various cancers. Moreover, expression level of this lncRNA in tumoral tissues has been associated with survival of patients. Consequently, this lncRNA might be regarded as biomarker for patients' follow-up.

Long non-coding RNAs (lncRNAs) constitute a large proportion of human transcriptome and are involved in fundamental aspects of neurodevelopment. In the present study, we evaluated expression levels of three lncRNAs, namely, Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), p21-associated ncRNA DNA damage–activated (PANDA), and taurine-upregulated gene 1 (TUG1), in peripheral blood of autism spectrum disorder (ASD) patients compared with those in healthy subjects. We found a significant upregulation of NEAT1 and TUG1 in ASD patients. In addition, relative expressions of the pairs of lncRNAs were significantly correlated in both patients and healthy subjects. However, expressions of these lncRNAs were not correlated with age of study participants. The present study provides further evidences for dysregulation of lncRNAs in ASD patients.

The nuclear paraspeckle assembly transcript 1 (NEAT1, a long non-coding RNA) is frequently overexpressed in human tumors, and higher NEAT1 expression is correlated with worse survival in cancer patients. NEAT1 drives tumor initiation and progression by modulating the expression of genes involved in the regulation of tumor cell growth, migration, invasion, metastasis, epithelial-to-mesenchymal transition, stem cell-like phenotype, chemoresistance and radioresistance, indicating the potential for NEAT1 to be a novel diagnostic biomarker and therapeutic target. Mechanistically, NEAT1 functions as a scaffold RNA molecule by interacting with EZH2 (a subunit of the polycomb repressive complex) to influence the expression of downstream effectors of EZH2, it also acts as a microRNA (miRNA) sponge to suppress the interactions between miRNAs and target mRNAs, and affects the expression of miR-129 by promoting the DNA methylation of the miR-129 promoter region. Knockdown of NEAT1 via small interfering RNA or short hairpin RNA inhibits the malignant behavior of tumor cells. In this review, we highlight the latest insights into the expression pattern, biological roles and mechanisms underlying the function and regulation of NEAT1 in tumors, and especially focus on its clinical implication as a new diagnostic biomarker and an attractive therapeutic target for cancers.

Paraspeckles are nuclear condensates, or membranelees organelles, that are built on the long noncoding RNA, NEAT1, and have been linked to many diseases. Although originally described as constitutive structures, here, in reviewing this field, we develop the hypothesis that cells increase paraspeckle abundance as part of a general stress response, to aid pro-survival pathways. Paraspeckles increase in many scenarios: when cells transform from one state to another, become infected with viruses and bacteria, begin to degenerate, under inflammation, in aging, and in cancer. Cells increase paraspeckles by increasing transcription of NEAT1 and adjusting its RNA processing. These increases in NEAT1 are driven by numerous stress-sensing signaling pathways, including signaling to mitochondria and stress granules, revealing crosstalk between the cytoplasm and nucleoplasm in the stress response. Thus, paraspeckles are an important piece of the puzzle in cellular homeostasis, and could be considered RNA-scaffolded nuclear equivalents of dynamic stress-induced structures that form in the cytoplasm. We speculate that, in general, cells rely on phase-separated paraspeckles to transiently tweak gene regulation in times of cellular flux.

Background Long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) plays a regulatory role in many biological processes; however, its role in cataracts has yet to be illuminated. This study aimed to investigate the protective role of NEAT1 in hydrogen peroxide (H2O2)-treated human lens epithelial cells (HLECs) and its underlying molecular mechanism. Methods HLECs (SRA01/04) were treated with 300 µM H2O2 to mimic cataract in vitro. Cell viability was detected by performing an MTT assay and EdU staining. Flow cytometry was carried out to detect apoptosis of HLECs. DNA damage was examined using γ-H2A histone family member X staining. and reactive oxygen species (ROS) production was measured using 2',7'dichlorofluorescin diacetate staining. The expression levels of lncRNA and proteins were detected with quantitative real-time polymerase chain reaction and western blot, respectively. Results The expression of NEAT1 was observed to be increased in H2O2-treated HLECs and age-related cataract (ARC) tissues. Knockdown NEAT1 strongly protected against H2O2-induced cell death and also regulated the expression of cleaved caspase-3, B-cell lymphoma 2, and Bcl-2-associated X protein. Further, knockdown NEAT1 also significantly suppressed H2O2-induced intracellular ROS production and malondialdehyde (MDA) content, but elevated the glutathione (GSH) activity of H2O2-treated cells. Also, it is demonstrated that si-NEAT1 greatly inhibited H2O2-induced phosphorylation of NF-кB p65 and p38 MAPK. Conclusions This study confirmed that knockdown NEAT1 attenuated H2O2-induced damage in HLECs, and inhibited the oxidative stress and apoptosis of HLECs via regulating nuclear factor-kappa B (NF-κB) p65 and p38 MAPK signaling. It may provide a potential target for clinical treatment of cataracts.

Huntington's disease (HD) is a devastating neurodegenerative disease caused by cytosine-adenine-guanine trinucleotide repeat expansion in the huntingtin gene. Growing evidence supports the regulatory functions of long noncoding RNAs (lncRNAs) in the disease process, but little is known about the association between lncRNAs and neuronal death in HD. Here, we evaluated the altered expression profiles of lncRNA in HD by using microarrays. Among dysregulated lncRNAs, we focused on the upregulation of nuclear paraspeckle assembly transcript 1 (NEAT1). Quantitative PCR analysis validated increased NEAT1 levels in the R6/2 mouse brain as well as the human HD postmortem brain. To determine the biological effects of NEAT1 on neuronal survival, neuro2A cells were transfected with the NEAT1 short isoform vector and were subjected to H2O2-induced injury. Subsequently, NEAT1-transfected cells showed increased viability under oxidative stress. Our observations support the notion that NEAT1 upregulation in HD contributes to the neuroprotective mechanism against neuronal injury rather than the pathological process underlying neurodegeneration in HD.

p54(nrb)/NonO is a nuclear RNA-binding protein involved in many cellular events such as pre-mRNA processing, transcription, and nuclear retention of hyper-edited RNAs. In particular, it participates in the splicing process by directly binding the 5' splice site of pre-mRNAs. The protein also concentrates in a nuclear body called paraspeckle by binding a G-rich segment of the ncRNA NEAT1. The N-terminal section of p54(nrb)/NonO contains tandem RNA recognition motifs (RRMs) preceded by an HQ-rich region including a threonine residue (Thr15) whose phosphorylation inhibits its RNA binding ability, except for G-rich RNAs. In this work, our goal was to understand the rules that characterize the binding of the p54(nrb)/NonO RRMs to their RNA target. We have done in vitro RNA binding experiments which revealed that only the first RRM of p54(nrb)/NonO binds to the 5' splice site RNA. We have then determined the structure of the p54(nrb)/NonO RRM1 by liquid-state NMR which revealed the presence of a canonical fold (β1α1β2β3α2β4) and the conservation of aromatic amino acids at the protein surface. We also investigated the dynamics of this domain by NMR. The p54(nrb)/NonO RRM1 displays some motional properties that are typical of a well-folded protein with some regions exhibiting more flexibility (loops and β-strands). Furthermore, we determined the affinity of p54(nrb)/NonO RRM1 interaction to the 5' splice site RNA by NMR and fluorescence quenching and mapped its binding interface by NMR, concluding in a classical nucleic acid interaction. This study provides an improved understanding of the molecular basis (structure and dynamics) that governs the binding of the p54(nrb)/NonO RRM1 to one of its target RNAs.

Nuclear proteins are often given a concise title that captures their function, such as ‘transcription factor,’ ‘polymerase’ or ‘nuclear-receptor.’ However, for members of the Drosophila behavior/human splicing (DBHS) protein family, no such clean-cut title exists. DBHS proteins are frequently identified engaging in almost every step of gene regulation, including but not limited to, transcriptional regulation, RNA processing and transport, and DNA repair. Herein, we present a coherent picture of DBHS proteins, integrating recent structural insights on dimerization, nucleic acid binding modalities and oligomerization propensity with biological function. The emerging paradigm describes a family of dynamic proteins mediating a wide range of protein–protein and protein–nucleic acid interactions, on the whole acting as a multipurpose molecular scaffold. Overall, significant steps toward appreciating the role of DBHS proteins have been made, but we are only beginning to understand the complexity and broader importance of this family in cellular biology.

Long noncoding RNAs (lncRNAs) have recently emerged as pivotal regulators in governing fundamental biological processes, as well as in tumorigenesis. The nuclear paraspeckle assembly transcript 1 (NEAT1) is one of the most highly regulated lncRNAs in recent genomic datasets, however, its biological role and regulatory mechanism in ovarian cancer (OC) development and progression are poorly defined. In this study, we identified that NEAT1 was up‐regulated in OC patients and cell lines, and its expression was associated with the FIGO stage and lymph node metastasis. Furthermore, the ectopic expression of NEAT1_1 in OVCAR‐3 cell lines promoted cell proliferation and invasion, whereas knockdown of NEAT1_1 did the opposite. Furthermore, NEAT1_1 was stabilized by an RNA‐binding protein HuR, but suppressed by miR‐124‐3p in OC cells. Accordingly, the increased HuR mRNA and decreased miR‐124‐3p levels were observed in OC patients. These results suggested that lncRNA NEAT1, whose expression was collaboratively controlled by HuR and miR‐124‐3p, could regulate ovarian carcinogenesis and may serve as a potential target for antineoplastic therapies.

Paraspeckles are subnuclear structures that assemble on nuclear paraspeckle assembly transcript 1 (NEAT1) long noncoding (lnc)RNA. Paraspeckle formation requires appropriate NEAT1 biogenesis and subsequent assembly with multiple prion-like domain (PLD) containing RNA-binding proteins. We found that SWI/SNF chromatin remodeling complexes function as paraspeckle components that interact with paraspeckle proteins (PSPs) and NEAT1. SWI/SNF complexes play an essential role in paraspeckle formation that does not require their ATP-dependent chromatin remodeling activity. Instead, SWI/SNF complexes facilitate organization of the PSP interaction network required for intact paraspeckle assembly. SWI/SNF complexes may collectively bind multiple PSPs to recruit them onto NEAT1. SWI/SNF complexes are also required for Sat III (Satellite III) lncRNA-dependent formation of nuclear stress bodies under heat shock conditions. Organization of the lncRNA-dependent omega speckle in Drosophila also depends on the chromatin remodeling complex. These findings raise the possibility that a common mechanism controls the formation of lncRNA-dependent nuclear body architecture.

Paraspeckles are subnuclear particles involved in the regulation of mRNA expression. They are formed by the association of DBHS family proteins and the NEAT1 long noncoding RNA. Here, we show that a recently identified structural motif, the charged single α-helix, is largely conserved in the DBHS family. Based on the available structural data and a previously suggested multimerization scheme of DBHS proteins, we built a structural model of a (PSPC1/NONO)n multimer that might have relevance in paraspeckle formation. Our model contains an extended coiled-coil region that is followed by and partially overlaps with the predicted charged single α-helix. We suggest that the charged single α-helix can act as an elastic ruler governing the exact positioning of the dimeric core structures relative to each other during paraspeckle assembly along the NEAT1 noncoding RNA.

The importance of membraneless organelles and these formation mechanisms, liquid-liquid phase separation (LLPS) has recently gained large attention due to new understandings on their roles in cellular functions including transcription, RNA splicing and signal transduction. Paraspeckles are well-known membraneless organelless located in the interchromatin space of mammalian cell nuclei and consist of multiple proteins and RNAs, including NONO, SFPQ and NEAT1. These paraspeckle components are highly expressed in hematopoietic cells. However, their roles in hematopoiesis are largely unknown. In this study, we found an unexpected involvement of epigenetic regulator ASXL1 in paraspeckle formation in hematopoietic cells. ASXL1 has a long intrinsically disordered region (IDR) in its C-terminal region and forms phase-separated droplets in vitro. Of note, a large part of the IDR is located behind the mutational hotspot of ASXL1 gene, suggesting that most pathogenic ASXL1mutants lack IDR. Interestingly, the mutant ASXL1 (ASXL1-MT) lacking its C-terminal IDR could not form droplets efficiently. ASXL1 upregulates NEAT1 expression and increases NONO-NEAT1 interaction, while a pathogenic ASXL1-MT does not support the interaction among paraspeckle components. Consequently, we observed disruption of paraspeckles and aberrant localization of Nono in cytoplasm of hematopoietic stem and progenitor cells (HSPCs) derived from ASXL1-MT knockin mice. We also showed that NONO depletion and forced expression of cytoplasmic NONO impair repopulating potential of HSPCs as ASXL1-MT does. The present findings highlight the potentially important role of paraspeckles in hematopoiesis and hematopoietic disorders.

BACKGROUND Spinal cord injury (SCI) is a debilitating neuropathological condition that significantly affects the quality of life. The present study is basic research examining the underlying mechanisms of NEAT1 and miR-29a in regulating LPS-induced PC-12 cell injury. MATERIAL AND METHODS The model of cell injury was induced by the treatment of PC-12 cells with LPS. The expressions of NEAT1, miR-29a, and inflammatory cytokines were measured by real-time quantitative polymerase chain reactions (RT-qPCR). Cell proliferation and apoptosis were evaluated by CCK-8 and flow cytometry, respectively. Finally, the target between miR-29a and NEAT1 as well as miR-29a and BCL2L11 was investigated by luciferase and RNA pull-down assays. RESULTS Knockdown of NEAT1 can inhibit inflammatory cytokine expression and PC-12 cell apoptosis and promote PC-12 cell proliferation by targeting miR-29a. However, the variation caused by NEAT1 knockdown can be reversed by the silencing of miR-29a and the overexpression of BCL2L11, which is the direct target gene of miR-29a. CONCLUSIONS High NEAT1 levels can increase LPS-induced injury in PC-12 cells through the miR-29a/BCL2L11 pathway. lncRNA NEAT1 may, therefore, be a promising target for SCI treatment.

Nuclear paraspeckle assembly transcript 1 (NEAT1) is a long non-coding RNA (lncRNA) reported to be frequently deregulated in various types of cancers and neurodegenerative processes. NEAT1 is an indispensable structural component of paraspeckles (PSs), which are dynamic and membraneless nuclear bodies that affect different cellular functions, including stress response. Furthermore, increasing evidence supports the crucial role of NEAT1 and essential structural proteins of PSs (PSPs) in the regulation of the DNA damage repair (DDR) system. This review aims to provide an overview of the current knowledge on the involvement of NEAT1 and PSPs in DDR, which might strengthen the rationale underlying future NEAT1-based therapeutic options in tumor and neurodegenerative diseases.

Polyglutamine (polyQ) repeat diseases are a class of neurodegenerative disorders caused by CAG-repeat expansion. There are diverse cellular mechanisms behind the pathogenesis of polyQ disorders, including transcriptional dysregulation. Interestingly, we find that levels of the long isoform of nuclear paraspeckle assembly transcript 1 (Neat1L) are elevated in the brains of mouse models of spinocerebellar ataxia types 1, 2, 7 and Huntington's disease (HD). Neat1L was also elevated in differentiated striatal neurons derived from HD knock-in mice and in HD patient brains. The elevation was mutant Huntingtin (mHTT) dependent, as knockdown of mHTT in vitro and in vivo restored Neat1L to normal levels. In additional studies, we found that Neat1L is repressed by methyl CpG binding protein 2 (MeCP2) by RNA-protein interaction but not by occupancy of MeCP2 at its promoter. We also found that NEAT1L overexpression protects from mHTT-induced cytotoxicity, while reducing it enhanced mHTT-dependent toxicity. Gene set enrichment analysis of previously published RNA sequencing data from mouse embryonic fibroblasts and cells derived from HD patients shows that loss of NEAT1L impairs multiple cellular functions, including pathways involved in cell proliferation and development. Intriguingly, the genes dysregulated in HD human brain samples overlap with pathways affected by a reduction in NEAT1, confirming the correlation of NEAT1L and HD-induced perturbations. Cumulatively, the role of NEAT1L in polyQ disease model systems and human tissues suggests that it may play a protective role in CAG-repeat expansion diseases.

In response to vascular injury, vascular smooth muscle cells (VSMCs) may switch from a contractile to a proliferative phenotype thereby contributing to neointima formation. Previous studies showed that the long noncoding RNA (lncRNA) NEAT1 is critical for paraspeckle formation and tumorigenesis by promoting cell proliferation and migration. However, the role of NEAT1 in VSMC phenotypic modulation is unknown. Herein we showed that NEAT1 expression was induced in VSMCs during phenotypic switching in vivo and in vitro. Silencing NEAT1 in VSMCs resulted in enhanced expression of SM-specific genes while attenuating VSMC proliferation and migration. Conversely, overexpression of NEAT1 in VSMCs had opposite effects. These in vitro findings were further supported by in vivo studies in which NEAT1 knockout mice exhibited significantly decreased neointima formation following vascular injury, due to attenuated VSMC proliferation. Mechanistic studies demonstrated that NEAT1 sequesters the key chromatin modifier WDR5 (WD Repeat Domain 5) from SM-specific gene loci, thereby initiating an epigenetic “off” state, resulting in down-regulation of SM-specific gene expression. Taken together, we demonstrated an unexpected role of the lncRNA NEAT1 in regulating phenotypic switching by repressing SM-contractile gene expression through an epigenetic regulatory mechanism. Our data suggest that NEAT1 is a therapeutic target for treating occlusive vascular diseases.

The molecular mechanisms of toxicity of chemically modified phosphorothioate antisense oligonucleotides (PS-ASOs) are not fully understood. Here, we report that toxic gapmer PS-ASOs containing modifications such as constrained ethyl (cEt), locked nucleic acid (LNA) and 2'-O-methoxyethyl (2'-MOE) bind many cellular proteins with high avidity, altering their function, localization and stability. We show that RNase H1-dependent delocalization of paraspeckle proteins to nucleoli is an early event in PS-ASO toxicity, followed by nucleolar stress, p53 activation and apoptotic cell death. Introduction of a single 2'-O-methyl (2'-OMe) modification at gap position 2 reduced protein-binding, substantially decreasing hepatotoxicity and improving the therapeutic index with minimal impairment of antisense activity. We validated the ability of this modification to generally mitigate PS-ASO toxicity with more than 300 sequences. Our findings will guide the design of PS-ASOs with optimal therapeutic profiles.

Retinoblastoma (RB) is an aggressive eye cancer of infancy and childhood with high mortality. Studies have shown that long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) is closely related to the progression of multiple cancers. However, its role in RB remains unknown. This study aimed to investigate the role and underlying mechanism of NEAT1 in RB. We first detected the expression of NEAT1 in human RB tissues and cell lines. The effects of NEAT1 on the proliferation, migration, and apoptosis of RB cells were analyzed by loss-of-function. The underlying mechanism of NEAT1 in RB was mainly focused on the microRNA 204/C-X-C chemokine receptor type 4 (miR-204/CXCR4) axis. In addition, the role and mechanism of NEAT1 in RB were further evaluated in a mouse xenograft tumor model. We found NEAT1 and CXCR4 expression levels were elevated, whereas miR-204 expression was decreased in RB tissues and cells. Downregulation of NEAT1 significantly decreased the proliferation and migration but promoted the apoptosis of RB cells. NEAT1 functioned as a competing endogenous RNA for miR-204 to regulate CXCR4 expression. Knockdown of NEAT1 suppressed the tumor volume, tumor weight, and CXCR4 expression, whereas increased miR-204 expression in mice. In conclusion, NEAT1 promotes the development of RB via miR-204/CXCR4 axis, which provides a new target for the treatment of RB disease.

Evidence has accumulated demonstrating that long noncoding RNAs (lncRNAs) participate in the initiation and progression of cancers. In this study, we found that the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) is significantly increased in both cervical cancer tissues and cell lines. Overexpression of NEAT1 promoted the proliferation and migration of cervical cancer cells. Molecular studies uncovered that NEAT1 functions as competitive endogenous RNA (ceRNA), binding the micro-RNA miR-9-5p and suppressing its expression. However, we consistently found that when NEAT1 was highly expressed, it attenuated the inhibitory effect of miR-9-5p on the expression of PTEN and POU2F1, which are the targets of miR-9-5p. Consistent with the negative regulation of NEAT1 on miR-9-5p, restoration of miR-9-5p inhibited the growth-promoting effects of NEAT1 on cervical cancer cells. Taken together, these results indicated that NEAT1 plays an important role in the regulation cervical cancer cell growth by targeting miR-9-5p. Our findings characterized the possible mechanism of NEAT1 in cervical cancer.

Paraspeckles are sub-nuclear structures found in the interchromatin space of mammalian cells. The core paraspeckle components include a lncRNA NEAT1 and members of the DBHS family of proteins: NONO, SFPQ, and PSPC1. Paraspeckles and their components play diverse roles in gene regulatory networks, including transcription, alternative RNA splicing, nuclear retention of RNA, and DNA repair. Although a previous study showed the presence of paraspeckles in hematopoietic stem and progenitor cells (HSPCs), their roles in normal and malignant hematopoiesis remain largely unknown. ASXL1 regulates gene expression through interactions with multiple epigenetic regulators. Somatic mutations in ASXL1 gene occur frequently in myeloid neoplasms. We previously generated a hematopoietic lineage-specific conditional knockin (KI) mouse of a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), and showed that ASXL1-MT inhibited repopulating capability of HSPCs. We performed deep RNA sequencing using HSPCs from ASXL1-MT-KI mice, and found aberrant alternative splicing in multiple genes involved in hematopoiesis. The altered splicing in ASXL1-MT-KI HSPCs included abnormal exon skipping or retention in Runx1, Traf6, Atm, and Dnmt3b. These findings, together with a previous report showing that ASXL1 mutations affect alternative splicing in U937 cells, strongly indicate the involvement of ASXL1 in RNA splicing machinery. Because a previous interactome analysis suggested the association between NONO and ASXL1, we hypothesized that ASXL1 may play a role in RNA maturation processes through interactions with paraspeckle proteins. To test this hypothesis, we examined physical and functional interactions between paraspeckle components and ASXL1. We found that both wild-type and mutant ASXL1 interact with NONO and SFPQ in 293T cells. Interestingly, protein and RNA immunoprecipitation (RIP) analyses revealed that coexpression of wild-type ASXL1, but not mutant ASXL1, enhanced interactions between NONO and histone H3 as well as NONO and NEAT1. These results suggest that ASXL1 acts as a scaffolding protein that assembles paraspeckle proteins and histones to promote transcription and RNA processing. Importantly, mutant ASXL1 loses this function. Next, we assessed subcellular localization of Nono in HSPCs from control and ASXL1-MT-KI mice. We observed predominant cytoplasmic expression of Nono in ASXL1-MT KI HSPCs, while Nono mainly localized in the nucleus in control cells (Figure 1). In addition, expression of NEAT1_2 isoform, which is essential for paraspeckle formation and maintenance, was substantially downregulated in ASXL1-MT-KI HSPCs. Consistent with these observations, RNA FISH against NEAT1 and immunofluorescence against NONO revealed disrupted paraspeckle formation in ASXL1-MT-KI HSPCs. These data suggest that ASXL1-MT promotes nuclear export of Nono, which results in disruption of paraspeckles in HSPCs. NONO has nuclear localization signal (NLS) at its C-terminus, and it was previously shown that a cytoplasmic C-truncated form of NONO induced senescence in fibroblasts. To assess the effect of forced expression of the cytoplasmic NONO in hematopoietic cells, we transduced vector or a NONO mutant lacking the NLS domain (NONO-ΔNLS) into c-Kit+ bone marrow cells, and transplanted these cells into recipient mice. NONO-ΔNLS induced overproduction of reactive oxygen species (ROS) and reduced engraftment of bone marrow progenitors as ASXL1-MT did. We then assessed the effect of Nono depletion in ASXL1-MT-KI HSPCs using CRISPR/Cas9 system. We crossed ASXL1-MT-KI mice with Rosa26-LSL-Cas9-KI mice, and c-Kit+ bone marrow cells derived from these mice were transduced with a non-targeting or Nono-targeting sgRNAs. This experiment revealed that Nono depletion reverted the impaired repopulation of ASXL1-MT-KI HSPCs after transplantation. Taken together, these data indicate that the cytoplasmic localization of Nono induced by ASXL1-MT has the negative impact on HSPC function. In summary, this study reveals a novel link between an epigenetic regulator ASXL1 and paraspeckle formation. The aberrant interaction between mutant ASXL1 and NONO results in NONO mislocalization, paraspeckle disruption and HSPC dysfunction. Our findings also suggest potentially important roles for paraspeckles to maintain normal hematopoiesis. Disclosures Ogawa: Qiagen Corporation: Patents & Royalties; RegCell Corporation: Equity Ownership; Asahi Genomics: Equity Ownership; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; Kan Research Laboratory, Inc.: Consultancy.

The formation of paraspeckle, a stress-induced nuclear body, increases in response to viral infection or proinflammatory stimuli. Paraspeckle consists of lncRNA (nuclear paraspeckle assembly transcript 1, NEAT1) and protein components including NONO, SFPQ, PSPC1, etc., which are shown to be involved in viral infection and cancer. Both NEAT1 and NONO expression increase in human hepatocellular carcinoma (HCC) samples according to TCGA data. However, the role of paraspeckle in HCC progression needs further identification. IL-6 signaling is well known to contribute to HCC progression. Here we reported that IL-6 signaling increased paraspeckle formation in HCC cells. Destruction of paraspeckle formation by silencing the paraspeckle essential components NEAT1_2 or NONO could suppress IL-6-induced STAT3 phosphorylation in HCC cells, and consequently repressed IL-6-promoted in vitro HCC cell invasion, cell cycle progression and survival. Mechanistically, paraspeckle promotes IL-6-induced STAT3 phosphorylation by binding and trapping peroxiredoxin-5 (PRDX5) mRNA in nucleus, decreasing protein level of PRDX5 which can directly interact with STAT3 and inhibit STAT3 phosphorylation. Besides, glutathione S-transferase P (GSTP1) protein, which inhibits DNA damage and apoptosis through its detoxification and anti-oxidation function, was also trapped within paraspeckles under IL-6 stimulation. Paraspeckle-trapping of both PRDX5 mRNA and GSTP1 protein contributes to IL-6-increased DNA damage in HCC cells. Our results demonstrate that paraspeckle can nuclear entrap the inhibitors of IL-6/STAT3 signaling as well as DNA damage, and then strengthen the promoting effect on HCC progression by IL-6. Therefore, paraspeckle contributes to the inflammation-related HCC progression and might be a potential therapeutic target for HCC.

Proteins and RNAs inside the cell nucleus are organized into distinct phases, also known as liquid-liquid phase separated (LLPS) droplet organelles or nuclear bodies. These regions exist within the spaces between chromatin-rich regions but their function is tightly linked to gene activity. They include major microscopically-observable structures such as the nucleolus, paraspeckle and Cajal body. The biochemical and assembly factors enriched inside these microenvironments regulate chromatin structure, transcription, and RNA processing, and other important cellular functions. Here, we describe published evidence that suggests nuclear bodies are bona fide LLPS droplet organelles and major regulators of the processes listed above. We also outline an updated "Supply or Sequester" model to describe nuclear body function, in which proteins or RNAs are supplied to surrounding genomic regions or sequestered away from their sites of activity. Finally, we describe recent evidence that suggests these microenvironments are both reflective and drivers of diverse pathophysiological states.

The aim of this study was to determine the function of the NEAT1/miR-23a-3p/SMC1A axis in cell proliferation and apoptosis in acute myeloid leukemia (AML). Microarray analysis was used to screen differentially expressed lncRNAs/miRNAs/mRNAs in primary AML cells. The expression of nuclear paraspeckle assembly transcript 1 (NEAT1), miR-23a-3p, and structural maintenance of chromosome 1 alpha (SMC1A) in primary AML cells and THP-1 cells were measured by quantitative real-time polymerase chain reaction (qRT-PCR). A Cell Counting Kit-8 (CCK-8) assay was used to analyze proliferation. Cell cycle progression and apoptosis were examined by flow cytometry. RNA immunoprecipitation (RIP) and dual-luciferase assays were performed to determine the correlation between miR-23a-3p and NEAT1 or SMC1A. The qRT-PCR illustrated that NEAT1 and SMC1A expression was decreased but that miR-23a-3p expression was increased in primary AML cells and THP-1 cells compared with that in normal cells. The RIP assay and dual-luciferase assay revealed the targeting relationship between miR-23a-3p and NEAT1 or SMC1A. The CCK-8 assay showed that the overexpression of NEAT1 and SMC1A or repression of miR-23a-3p inhibited cell proliferation. Flow cytometry showed that the upregulation of NEAT1 and SMC1A or repression of miR-23a-3p promoted apoptosis and affected the cell cycle. NEAT1 repressed the expression of miR-23a-3p, and therefore promoted SMC1A, which in turn suppressed myeloid leukemia cell proliferation and enhanced apoptosis.

The nuclear paraspeckle assembly transcript 1 (abbreviated as NEAT1), a nuclear sufficient long noncoding RNA (abbreviated as lncRNA), has aroused a rising concern in recent years. As uncovered by reports, the increase in NEAT1 is related to the deteriorated prognosis of lung cancer, breast cancer, hepatocellular cancer, and colorectal cancer (abbreviated as CRC). Thus far, the mechanism of NEAT1 has not been elucidated by the existing researches. The impact of knockdown of both NEAT1 and its predicted downstream miR‐193a‐3p in CRC cells was examined here to delve into their interactions and mechanisms. Additionally, the target of miR‐193a‐3p, Kirsten rat sarcoma viral oncogene homolog (abbreviated as KRAS), was also predicted by bioinformatics algorithms. Small interfering RNA and antisense oligonucleotides that inhibit NEAT1, as well as overexpression or knockdown of miR‐193a‐3p, were adequately drawn upon to confirm that NEAT1 serves as a miR‐193a‐3p sponge or competing endogenous RNA, to impact miR‐193a‐3p's further functions, including modulating KRAS proteins, both in vitro and in vivo. Generally, lncRNA NEAT1/hsa‐miR‐193a‐3p/KRAS axis was substantiated in CRC cells and could provide novel insight into both diagnostic and therapeutic advancement in CRC.

The Hepatitis Delta Virus (HDV) relies mainly on host proteins for its replication. We previously identified that PSF and p54nrb associate with the HDV RNA genome during viral replication. Together with PSP1, these proteins are part of paraspeckles, which are subnuclear bodies nucleated by the long non-coding RNA NEAT1. In this work, we established the requirement for PSF, p54nrb and PSP1 in HDV replication using RNAi-mediated knockdown in HEK-293 cells replicating the HDV RNA genome. We determined that HDV replication induces the delocalization of PSP1 to cytoplasmic foci containing PABP and increases NEAT1 level causing an enlargement of NEAT1 foci. Overall, our data support a role for the main paraspeckles proteins in HDV life cycle and indicate that HDV replication causes a cellular stress and induces both a delocalization of the PSP1 to the cytoplasm and a disruption of paraspeckles.

Herpesviruses have developed a variety of sophisticated immune evasion strategies to establish lifelong latent infection, including the use of long non-coding RNAs (lncRNAs). In this review, we summarize the lncRNA action modes, i.e., RNA–protein, RNA–RNA, and RNA–DNA interactions, involved in regulating important aspects of immunity by controlling gene expression at various stages. Upon herpesvirus infection, host lncRNAs, such as nuclear paraspeckle assembly transcript 1, negative regulator of antiviral, and B-cell integration cluster have been functionally characterized as negative or positive antiviral regulators in the immune response. Herpesviruses have also evolved multiple strategies to modulate the host immune response using lncRNAs, such as latency-associated transcript, β 2.7 RNA, 5 kb and 7.2 kb lncRNAs, Epstein–Barr virus-encoded non-coding RNA, BamH I-A rightward transcripts, polyadenylated nuclear, and herpesvirus saimiri U-rich RNAs. We discuss the various mechanisms of immune-related lncRNAs, and their diversified and important functions in the modulation of innate and adaptive immunity upon herpesvirus infection as well as in host–pathogen interactions, which will facilitate our understanding of rational design of novel strategies to combat herpesvirus infection.

The roles of transforming growth factor β (TGF-β) depend on the cellular context. Paraspeckle component 1 now arises as a driver of epithelial-to-mesenchymal transition and stemness transcription factors to redirect effectors from tumour suppressive to pro-metastatic gene promoters, emerging as a contextual determinant of TGF-β function.

Nuclear paraspeckle assembly transcript 1 (NEAT1), a long non-coding RNA (lncRNA), is a core structural component of paraspeckles and is essential for paraspeckle formation. NEAT1 comprises two different isoforms: NEAT1_1 (3.7 kb) and NEAT1_2 (23 kb). Recently, NEAT1 has been shown to have oncogenic roles and to facilitate tumorigenesis in various human cancers. However, the function of NEAT1 in papillary thyroid cancer (PTC) is not well understood. The relative expression levels of NEAT1_2, ATPase family AAA domain-containing protein 2 (ATAD2), and microRNA-106b-5p (miR-106b-5p) were assessed via quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Four PTC cell lines were used to detect the relative expression of NEAT1_2. The effects of NEAT1_2 on PTC cells were studied by RNA interference approaches in vitro. The effects of NEAT1_2 on downstream proteins were detected by western blotting. The underlying mechanism was clarified by a rescue experiment, and three dual-luciferase reporter assays. NEAT1_2 expression was markedly increased in PTC tissues and the PTC cell lines (K1 and TPC1). The relative expression level of NEAT1_2 was positively associated with TNM stage and tumor size. NEAT1_2 knockdown led to a significant inhibition of growth and metastasis, and induced apoptosis in PTC cells. Knockdown of NEAT1_2 significantly inhibited malignant biological behavior by downregulating the oncogene ATAD2. In addition, NEAT1_2 could act as a competing endogenous RNA to regulate the expression of ATAD2 through downregulating miR-106b-5p. Taken together, our results indicated that NEAT1_2 is overexpressed in PTC. NEAT1_2 could function as a competing endogenous RNA to regulate ATAD2 expression by sponging miR-106b-5p in PTC. Targeting NEAT1_2 could be a promising therapeutic strategy for patients with PTC.