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Long noncoding RNAs (lncRNAs) account for the largest portion of RNA from the transcriptome, yet most of their functions remain unknown. Here, we performed two independent high-throughput CRISPRi screens to understand the role of lncRNAs in monocyte function and differentiation. The first was a reporter-based screen to identify lncRNAs that regulate TLR4-NFkB signaling in human monocytes and the second screen identified lncRNAs involved in monocyte to macrophage differentiation. We successfully identified numerous noncoding and protein-coding genes that can positively or negatively regulate inflammation and differentiation. To understand the functional roles of lncRNAs in both processes, we chose to further study the lncRNA LOUP [lncRNA originating from upstream regulatory element of SPI1 (also known as PU.1)], as it emerged as a top hit in both screens. Not only does LOUP regulate its neighboring gene, the myeloid fate-determining factor SPI1, thereby affecting monocyte to macrophage differentiation, but knockdown of LOUP leads to a broad upregulation of NFkB-targeted genes at baseline and upon TLR4-NFkB activation. LOUP also harbors three small open reading frames capable of being translated and are responsible for LOUPs ability to negatively regulate TLR4/NFkB signaling. This work emphasizes the value of high-throughput screening to rapidly identify functional lncRNAs in the innate immune system.

Summary: MicroRNA827 (miR827) is functionally conserved among different plant species and displays species‐specific characteristics, but the mechanisms by which miR827 regulates phosphate (Pi) starvation tolerance and maize development remain elusive. We found that miR827 selectively targets the Pi transporter genes SPX‐MFS1 and SPX‐MFS5. miR827 overexpression improved the Pi starvation tolerance, plant architecture and grain yield and quality, whereas miR827 suppression yielded a contrasting phenotype. In addition, we identified a specific long noncoding RNA (lncRNA767) that serves as a direct target and a facilitator of miR827 and can stabilize the SPX‐MFS1 and SPX‐MFS5 transcripts, leading to their translation inhibition. The orchestrated regulation of SPX‐MFS1 and SPX‐MFS5 modulates PHR1; 1 and PHR1; 2, which are critical transcription factors in Pi signalling, and thereby affects the expression of downstream Pi starvation‐induced genes. Together, these findings demonstrate that miR827, assisted by lncRNA767, enhances SPX‐MFS1 and SPX‐MFS5 suppression and thus exerts a significant impact on Pi homeostasis and several essential agronomic traits of maize. [ABSTRACT FROM AUTHOR]

Background: Abnormal pulmonary vascular development poses significant clinical challenges for infants with bronchopulmonary dysplasia (BPD). Although numerous factors have been suggested to control the development of pulmonary blood vessels, the mechanisms underlying the role of long noncoding RNAs (lncRNAs) in this process remain unclear. Methods: A lncRNA array was used to measure the differential expression of lncRNAs in premature infants with and without BPD. The expression of lncRNA-VSIG2-1:1 in patients with BPD and hyperoxia-induced human pulmonary microvascular endothelial cells (HPMECs) was assessed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Fluorescence in situ hybridization (FISH) assay was performed to detect the subcellular localization of lncRNA-VSIG2-1:1. Pulmonary microvascular endothelial cells were stably transfected with adenoviral vectors to silence or overexpress lncRNA-VSIG2-1:1. The effects of lncRNA-VSIG2-1:1 on the proliferation, migration, and tube formation abilities of HPMECs subjected to hyperoxia were examined by performing Cell Counting Kit‐8 (CCK-8), cell migration, and tubule formation assays. RNA sequencing (RNA-seq) was performed to determine the correlation between lncRNA-VSIG2-1:1 and phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT). The protein levels of vascular endothelial growth factor (VEGF), p-PI3K, PI3K, p-AKT, and AKT were determined using western blotting. Results: The expression of lncRNA-VSIG2-1:1 was upregulated in patients with BPD and hyperoxia-treated HPMECs. Inhibiting lncRNA-VSIG2-1:1 expression promoted the proliferation, migration, and tube-formation abilities of HPMECs, while significantly increasing VEGF, p-PI3K, and p-AKT levels. Conclusion: Our findings reveal that the suppression of lncRNA-VSIG2-1:1 expression stimulates angiogenesis in vitro by inducing the initiation of the VEGF/PI3K/AKT signaling pathway. This observation may aid the development of novel therapeutic targets for treating BPD. [ABSTRACT FROM AUTHOR]

Lowered muscle regenerative capacity in the elderly greatly contributes to the development of multiple diseases. The specific roles of long noncoding RNAs (lncRNAs) in muscle regenerative capacity during aging remain unknown. Here, we identify an elevated lncRNA (lncRNA-3), in association with reduced MyoD expression and suppressed muscle regenerative capacity, in the skeletal muscle of aged mice. LncRNA-3 could interact with both the MyoD1 promoter and RbAp46/48, a subunit of Polycomb repressive complex 2 (PRC2). LncRNA-3 could recruit PRC2 to the MyoD1 promoter and enhance the MyoD1 silencing, which, in turn, suppressed the muscle regenerative capacity. Muscle-specific lncRNA-3 knockdown could restore the muscle regenerative capacity in the aged mice. Exogenous RbAp46/48 binding motif (Rb-motif-2) treatment in skeletal muscle could compete for the lncRNA-3 binding, and therefore, enhance the muscle regenerative capacity in the aged mice. Taken together, lncRNA-3 requires PRC2 for MyoD1 silencing to suppress muscle regenerative capacity during aging. These findings provide a novel therapeutic target and a new strategy to elevate the muscle regenerative capacity in the aged population. [ABSTRACT FROM AUTHOR]

Progression of diabetic retinopathy resists arrest even after institution of intensive glycemic control, suggesting a "metabolic memory" phenomenon, but the mechanism responsible for this phenomenon is still elusive. Gene expression and biological processes can also be regulated by long noncoding RNAs (LncRNAs), the RNAs with >200 nucleotides and no open reading frame for translation, and several LncRNAs are aberrantly expressed in diabetes. Our aim was to identify retinal LncRNAs that fail to reverse after termination of hyperglycemia. Microarray analysis was performed on retinal RNA from streptozotocin‐induced diabetic rats in poor glycemic control for 8 months, followed by in good glycemic control (blood glucose >400 mg/dL), or for 4 months, with four additional months of good glycemic control (blood glucose <150 mg/dL). Differentially expressed LncRNAs and mRNAs were identified through Volcano filtering, and their functions were predicted using gene ontology and pathway enrichment analyses. Compared with age‐matched normal rats, rats in continuous poor glycemic control had >1479 differentially expressed LncRNAs (710 downregulated, 769 upregulated), and among those, 511 common LncRNAs had similar expression in Diab and Rev groups (139 downregulated, 372 upregulated). Gene Ontology/pathway analysis identified limited LncRNAs in biological processes, but analysis based on biological processes/molecular function revealed >350 genes with similar expression in Diab and Rev groups; these genes were mainly associated with stress response, cell death, mitochondrial damage and cytokine production. Thus, identifying retinal LncRNAs and their gene targets that do not benefit from termination of hyperglycemia have potential to serve as therapeutic targets to slow down the progression of diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) was identified as a malignant tumor with rising incidence and mortality rates, and the roles of long noncoding RNA (lncRNA) in CCA remained not entirely clear. In this study, LINC00511 had high expression in CCA, which was closely related to poor prognosis. Knockdown of LINC00511 significantly inhibited cell malignant biological behaviors. It also affected the stemness of CCA, evidenced by decreased SOX2 protein expression. Moreover, the study revealed the interaction of LINC00511, YTHDF2, and SOX2 in CCA. Specifically, LINC00511 facilitated the formation of a complex with YTHDF2 on SOX2 mRNA, which uniquely enhances the mRNA's stability through m6A methylation sites. This stabilization appears crucial for maintaining malignant behaviors in CCA cells. Additionally, LINC00511 modulated SOX2 expression via the PI3K/AKT signaling pathway. Meanwhile, SOX2 can also promote LINC00511 expression as an upstream transcription factor, thereby confirming a positive feedback loop formed by LINC00511, YTHDF2, and SOX2, which plays a significant role in the occurrence and development of CCA. Finally, the study successfully constructed two patient‐derived xenograft models, revealing the vital role of LINC00511 in CCA development. In summary, this research provides a comprehensive understanding of the role of LINC00511 in the pathogenesis of CCA. [ABSTRACT FROM AUTHOR]

More than 10% of adults in the United States have type 2 diabetes mellitus (DM) with a 2–4 times higher prevalence of ischemic heart disease than the non-diabetics. Despite extensive research approaches to limit this life-threatening condition have proven unsuccessful, highlighting the need for understanding underlying molecular mechanisms. Long noncoding RNAs (lncRNAs), which regulate gene expression by acting as signals, decoys, guides, or scaffolds have been implicated in diverse cardiovascular conditions. However, their role in ischemic heart disease in DM remains poorly understood. We provide new insights into the lncRNA expression profile after ischemic heart disease in DM mice. We performed unbiased RNA sequencing of well-characterized type 2 DM model db/db mice or its control db/+ subjected to sham or MI surgery. Computational analysis of the RNA sequencing of these LV tissues identified several differentially expressed lncRNAs between (db/db sham vs. db/db MI) including Gm19522 and Gm8075. lncRNA Gm-19522 may regulate DNA replication via DNA protein kinases, while lncRNA Gm-8075 is associated with cancer gene dysregulation and PI3K/Akt pathways. Thus, the downregulation of lncRNAs Gm19522 and Gm8075 post-MI may serve as potential biomarkers or novel therapeutic targets to improve cardiac repair/recovery in diabetic ischemic heart disease. [ABSTRACT FROM AUTHOR]

Background: The first 24 h of infection represent a critical time window in interactions between pathogens and host tissue. However, it is not possible to study such early events in human lung during natural infection due to lack of clinical access to tissue this early in infection. We, therefore, applied RNA sequencing to ex vivo cultured human lung tissue explants (HLTE) from patients with emphysema to study global changes in small noncoding RNA, mRNA, and long noncoding RNA (lncRNA, lincRNA) populations during the first 24 h of infection with influenza A virus (IAV), Mycobacterium bovis Bacille Calmette-Guerin (BCG), and Pseudomonas aeruginosa. Results: Pseudomonas aeruginosa caused the strongest expression changes and was the only pathogen that notably affected expression of microRNA and PIWI-associated RNA. The major classes of long RNAs (> 100 nt) were represented similarly among the RNAs that were differentially expressed upon infection with the three pathogens (mRNA 77–82%; lncRNA 15–17%; pseudogenes 4–5%), but lnc-DDX60-1, RP11-202G18.1, and lnc-THOC3-2 were part of an RNA signature (additionally containing SNX10 and SLC8A1) specifically associated with IAV infection. IAV infection induced brisk interferon responses, CCL8 being the most strongly upregulated mRNA. Single-cell RNA sequencing identified airway epithelial cells and macrophages as the predominant IAV host cells, but inflammatory responses were also detected in cell types expressing few or no IAV transcripts. Combined analysis of bulk and single-cell RNAseq data identified a set of 6 mRNAs (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) as the core transcriptomic response to IAV infection. The two bacterial pathogens induced qualitatively very similar changes in mRNA expression and predicted signaling pathways, but the magnitude of change was greater in P. aeruginosa infection. Upregulation of GJB2, VNN1, DUSP4, SerpinB7, and IL10, and downregulation of PKMYT1, S100A4, GGTA1P, and SLC22A31 were most strongly associated with bacterial infection. Conclusions: Human lung tissue mounted substantially different transcriptomic responses to infection by IAV than by BCG and P. aeruginosa, whereas responses to these two divergent bacterial pathogens were surprisingly similar. This HLTE model should prove useful for RNA-directed pathogenesis research and tissue biomarker discovery during the early phase of infections, both at the tissue and single-cell level. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are transcribed elements increasingly recognized for their roles in regulating gene expression. Thus far, however, we have little understanding of how lncRNAs contribute to evolution and adaptation. Here, we show that a conserved lncRNA, ivory, is an important color patterning gene in the buckeye butterfly Junonia coenia. ivory overlaps with cortex, a locus linked to multiple cases of crypsis and mimicry in Lepidoptera. Along with a companion paper by Livraghi et al., we argue that ivory, not cortex, is the color pattern gene of interest at this locus. In J. coenia, a cluster of cis-regulatory elements (CREs) in the first intron of ivory are genetically associated with natural variation in seasonal color pattern plasticity, and targeted deletions of these CREs phenocopy seasonal phenotypes. Deletions of different ivory CREs produce other distinct phenotypes as well, including loss of melanic eyespot rings, and positive and negative changes in overall wing pigmentation. We show that the color pattern transcription factors Spineless, Bric-a-brac, and Ftz-f1 bind to the ivory promoter during wing pattern development, suggesting that they directly regulate ivory. This case study demonstrates how cis-regulation of a single noncoding RNA can exert diverse and nuanced effects on the evolution and development of color patterns, including modulating seasonally plastic color patterns. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) in the endometrium of individuals with and without endometriosis (EMS) during the proliferative (P) and secretory (S) phases of the menstrual cycle. Tissues were obtained from 18 control (CT; P-phase [pCT], n = 8; S-phase [sCT], n = 13) and 23 EMS patients (P-phase [pEMS], n = 13; S-phase [sEMS], n = 12). DElncRNAs and DEmRNAs were analyzed using total RNA-sequencing. In P-phase, expression of NONHSAG019742.2 and NONHSAT120701.2 was significantly higher in EMS than control patients, that of while NONHSAG048398.2 and NONHSAG016560.2 was lower in EMS patients. In S-phase, expression of NONHSAT000959.2, NONHSAT203423.1, and NONHSAG053769.2 was significantly increased in EMS patients, while that of NONHSAG012105.2 and NONHSAG020839.2 was lower. In addition, the expression of HSD11B2, THBS1, GPX3, and SHISA6 was similar to that of neighboring lncRNAs in both P- and S-phases. In contrast, ELP3 and NR4A1, respectively, were up- or downregulated in pEMS tissues. In sEMS, expression of LAMB3 and HIF1A was increased, while expression of PAM was reduced. Our findings on lncRNAs and mRNAs encourage not only exploration of the potential clinical applications of lncRNAs and mRNAs as prognostic or diagnostic biomarkers for EMS but also to gain valuable insights into its pathogenesis. [ABSTRACT FROM AUTHOR]

Background and purpose: Long noncoding RNA (lncRNA) dysregulation has been reported to play a pivotal role in the development of cancers. In this study, we aimed to screen the key lncRNA in oral squamous cell carcinoma (OSCC) via bioinformatics analysis and further validate the function of lncRNA in vitro and in vivo. Methods: Bioinformatics analysis was conducted to identify differentially expressed lncRNAs between control and OSCC samples. Quantitative real-time–polymerase chain reaction was employed to detect the expression of differentially expressed lncRNAs in human tongue squamous cell carcinoma and human oral keratinocytes cell lines. The biological function of lncRNA and its mechanism were examined via the experimental assessment of the cell lines with the lncRNA overexpressed and silenced. Additionally, to further explore the function of lncRNA in the progression of OSCC, xenograft tumour mouse models were established using 25 mice (5 groups, each with 5 mice). Tumour formation was observed at 2 weeks after the cell injection, and the tumours were resected at 5 weeks post-implantation. Results: Two lncRNAs, LINC00958 and AFAP1-AS1, were found to be correlated with the prognosis of OSCC. The results of the quantitative real-time–polymerase chain reaction indicated that the 2 lncRNAs were highly expressed in OSCC. In combination with the previous literature, we found AFAP1-AS1 to be a potentially important biomarker for OSCC. Thus, we further investigated its biological function and found that AFAP1-AS1 silencing inhibited cell proliferation, migration, and invasion whereas AFAP1-AS1 overexpression reversed the effect of AFAP1-AS1 silencing (P < .05). Mechanism analysis revealed that AFAP1-AS1 regulated the development of OSCC through the ubiquitin-mediated proteolysis pathway. Conclusions: AFAP1-AS1 is an oncogene that aggravates the development of OSCC via the ubiquitin-mediated proteolysis pathway. It also provides a novel potential therapy for OSCC.

Abstract Background Abnormal pulmonary vascular development poses significant clinical challenges for infants with bronchopulmonary dysplasia (BPD). Although numerous factors have been suggested to control the development of pulmonary blood vessels, the mechanisms underlying the role of long noncoding RNAs (lncRNAs) in this process remain unclear. Methods A lncRNA array was used to measure the differential expression of lncRNAs in premature infants with and without BPD. The expression of lncRNA-VSIG2-1:1 in patients with BPD and hyperoxia-induced human pulmonary microvascular endothelial cells (HPMECs) was assessed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Fluorescence in situ hybridization (FISH) assay was performed to detect the subcellular localization of lncRNA-VSIG2-1:1. Pulmonary microvascular endothelial cells were stably transfected with adenoviral vectors to silence or overexpress lncRNA-VSIG2-1:1. The effects of lncRNA-VSIG2-1:1 on the proliferation, migration, and tube formation abilities of HPMECs subjected to hyperoxia were examined by performing Cell Counting Kit‐8 (CCK-8), cell migration, and tubule formation assays. RNA sequencing (RNA-seq) was performed to determine the correlation between lncRNA-VSIG2-1:1 and phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT). The protein levels of vascular endothelial growth factor (VEGF), p-PI3K, PI3K, p-AKT, and AKT were determined using western blotting. Results The expression of lncRNA-VSIG2-1:1 was upregulated in patients with BPD and hyperoxia-treated HPMECs. Inhibiting lncRNA-VSIG2-1:1 expression promoted the proliferation, migration, and tube-formation abilities of HPMECs, while significantly increasing VEGF, p-PI3K, and p-AKT levels. Conclusion Our findings reveal that the suppression of lncRNA-VSIG2-1:1 expression stimulates angiogenesis in vitro by inducing the initiation of the VEGF/PI3K/AKT signaling pathway. This observation may aid the development of novel therapeutic targets for treating BPD.

Abstract More than 10% of adults in the United States have type 2 diabetes mellitus (DM) with a 2–4 times higher prevalence of ischemic heart disease than the non-diabetics. Despite extensive research approaches to limit this life-threatening condition have proven unsuccessful, highlighting the need for understanding underlying molecular mechanisms. Long noncoding RNAs (lncRNAs), which regulate gene expression by acting as signals, decoys, guides, or scaffolds have been implicated in diverse cardiovascular conditions. However, their role in ischemic heart disease in DM remains poorly understood. We provide new insights into the lncRNA expression profile after ischemic heart disease in DM mice. We performed unbiased RNA sequencing of well-characterized type 2 DM model db/db mice or its control db/+ subjected to sham or MI surgery. Computational analysis of the RNA sequencing of these LV tissues identified several differentially expressed lncRNAs between (db/db sham vs. db/db MI) including Gm19522 and Gm8075. lncRNA Gm-19522 may regulate DNA replication via DNA protein kinases, while lncRNA Gm-8075 is associated with cancer gene dysregulation and PI3K/Akt pathways. Thus, the downregulation of lncRNAs Gm19522 and Gm8075 post-MI may serve as potential biomarkers or novel therapeutic targets to improve cardiac repair/recovery in diabetic ischemic heart disease.

The RNA modification N6-methyladenosine (m6A) regulates the interaction between RNA and various RNA binding proteins within the nucleus and other subcellular compartments and has recently been shown to be involved in experience-dependent plasticity, learning, and memory. Using m6A RNA-sequencing, we have discovered a distinct population of learning-related m6A- modified RNAs at the synapse, which includes the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (Malat1). RNA immunoprecipitation and mass spectrometry revealed 12 new synapse-specific learning-induced m6A readers in the mPFC of male C57/BL6 mice, with m6A-modified Malat1 binding to a subset of these, including CYFIP2 and DPYSL2. In addition, a cell type- and synapse-specific, and state-dependent, reduction of m6A on Malat1 impairs fear-extinction memory; an effect that likely occurs through a disruption in the interaction between Malat1 and DPYSL2 and an associated decrease in dendritic spine formation. These findings highlight the critical role of m6A in regulating the functional state of RNA during the consolidation of fear-extinction memory, and expand the repertoire of experience-dependent m6A readers in the synaptic compartment.SIGNIFICANCE STATEMENT We have discovered that learning-induced m6A-modified RNA (including the long noncoding RNA, Malat1) accumulates in the synaptic compartment. We have identified several new m6A readers that are associated with fear extinction learning and demonstrate a causal relationship between m6A-modified Malat1 and the formation of fear-extinction memory. These findings highlight the role of m6A in regulating the functional state of an RNA during memory formation and expand the repertoire of experience-dependent m6A readers in the synaptic compartment.

RNA is integral to the regulatory circuits that control cell identity and behavior. Cis-regulatory elements in mRNAs interact with RNA-binding proteins (RBPs) that can alter RNA sequence, stability, and translation into protein. Similarly, long noncoding RNAs (lncRNAs) scaffold ribonucleoprotein complexes that mediate transcriptional and post-transcriptional regulation of gene expression. Indeed, cell programming is fundamental to multicellular life and, in this era of cellular therapies, it is of particular interest in T cells. Here, we review key concepts and recent advances in our understanding of the RNA circuits and RBPs that govern mammalian T cell differentiation and immune function.

Abstract Background Disulfidptosis is an emerging form of cellular death resulting from the binding of intracellular disulfide bonds to actin cytoskeleton proteins. This study aimed to investigate the expression and prognostic significance of hub disulfidptosis-related lncRNAs (DRLRs) in R0 resected hepatocellular carcinoma (HCC) as well as their impact on the malignant behaviour of HCC cells. Methods A robust signature for R0 resected HCC was constructed using least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression and was validated in an independent internal validation cohort to predict the prognosis of R0 HCC patients. Comprehensive bioinformatics analysis was performed on the hub DRLRs (KDM4A-AS1, MKLN1-AS, and TMCC1-AS1), followed by experimental validation using quantitative real-time polymerase chain reaction (qRT‒PCR) and cellular functional assays. Results The signature served as an independent prognostic factor applicable to R0 HCC patients across different age groups, tumour stages, and pathological characteristics. Gene Ontology (GO) and gene set enrichment analysis (GSEA) revealed hub pathways associated with this signature. The high-risk group presented an increased abundance of M0 macrophages and activated memory CD4 T cells as well as elevated macrophage and major histocompatibility complex (MHC) class I expression. High-risk R0 HCC patients also presented increased tumour immune dysfunction and exclusion scores (TIDEs), mutation frequencies, and tumour mutational burdens (TMBs). Drug sensitivity analysis revealed that high-risk patients were more responsive to drugs, including GDC0810 and osimertinib. High expression levels of the three hub DRLRs were detected in R0 HCC tissues and HCC cell lines. Functional assays revealed that the three hub DRLRs enhanced HCC cell proliferation, migration, and invasion. Conclusions A signature was constructed on the basis of three DRLRs, providing novel insights for personalized precision therapy in R0 HCC patients. Graphical Abstract

Abstract Medulloblastoma, the most common malignant pediatric brain tumor, is classified into four main molecular subgroups, but group 3 and group 4 tumors are difficult to subclassify and have a poor prognosis. Rapid point-of-care diagnostic and prognostic assays are needed to improve medulloblastoma risk stratification and management. N6-methyladenosine (m6A) is a common RNA modification and long non-coding RNAs (lncRNAs) play a central role in tumor progression, but their impact on gene expression and associated clinical outcomes in medulloblastoma are unknown. Here we analyzed 469 medulloblastoma tumor transcriptomes to identify lncRNAs co-expressed with m6A regulators. Using LASSO-Cox analysis, we identified a five-gene m6A-associated lncRNA signature (M6LSig) significantly associated with overall survival, which was combined in a prognostic clinical nomogram. Using expression of the 67 m6A-associated lncRNAs, a subgroup classification model was generated using the XGBoost machine learning algorithm, which had a classification accuracy > 90%, including for group 3 and 4 samples. All M6LSig genes were significantly correlated with at least one immune cell type abundance in the tumor microenvironment, and the risk score was positively correlated with CD4+ naïve T cell abundance and negatively correlated with follicular helper T cells and eosinophils. Knockdown of key m6A writer genes METTL3 and METTL14 in a group 3 medulloblastoma cell line (D425-Med) decreased cell proliferation and upregulated many M6LSig genes identified in our in silico analysis, suggesting that the signature genes are functional in medulloblastoma. This study highlights a crucial role for m6A-dependent lncRNAs in medulloblastoma prognosis and immune responses and provides the foundation for practical clinical tools that can be rapidly deployed in clinical settings.

Abstract To study the degradation of lncRNAs in EPMI in rat brain tissue, this study provides a new direction for the estimation of EPMI. LncRNA high-throughput sequencing was performed on the brain tissues of hemorrhagic shock model rats at 0 h and 24 h, and the target lncRNAs were screened. Samples at 0, 1, 3, 6, 12, 18 and 24 h after death were collected, and miRNA-9 and miRNA-125b were used as reference genes. The relative expression levels of lncRNAs at each PMI were detected by RT–qPCR, and a functional model involving lncRNAs and EPMI was established. Samples were collected at 6, 9, 15, and 21 h after death for functional model verification. The expression of several lncRNAs decreased with the prolongation of EPMI, and the mathematical model established by several lncRNA indices exhibited good fit. The verification results of the multi-index joint function model are significantly better than those of the single-index function model, and the established model is more practical. There is a linear relationship between lncRNAs and EPMI, and the multi-index function model is significantly better than the single-index function model, which is important for EPMI inference in forensic pathology practice.

Abstract Background Pancreatic cancer (PaCa) is one of the most intractable and fatal malignancies and is associated with the dysregulation of long noncoding RNAs (lncRNAs), which are a large class of noncoding RNAs larger than 200 nt that act as competing endogenous RNAs or sponges for miRNAs to induce tumour biological behaviours. However, their clinical value in treating pancreatic cancer has been poorly explained, but they are essential for improving the prognosis of PaCa patients. Methods We analysed the plasma-derived exosomal lncRNA profiles of PaCa patients by using whole-transcriptome sequencing analysis and identified significantly differentially expressed lncRNAs, including LINC01268, LINC02802, AC124854.1, and AL132657.1. In the current study, the expression levels of four plasma-derived exosomal lncRNAs in PaCa plasma were validated via quantitative real-time polymerase chain reaction (qRT‒PCR). The relationship between the expression of the four lncRNAs and the clinicopathological features of patients with PaCa was also evaluated. Results We demonstrated that exosomal LINC01268, LINC02802, AC124854.1 and AL132657.1 were highly expressed in PaCa plasma compared with those in normal controls; moreover, they were positively correlated with the serum expression of carbohydrate antigen 19–9 (CA19-9). The receiver operating characteristic curves (AUCs) of the four lncRNAs were 0.8421, 0.6544, 0.7190, and 0.6321, and the AUC value of the combination of the four exosomal lncRNAs increased to 0.8476, with a sensitivity of 0.72 and specificity of 0.89. These results suggested that the plasma-derived exosomal genes LINC01268, LINC02802, AC124854.1, and AL132657.1 may be novel diagnostic markers for PaCa. Conclusions Our research demonstrated that the plasma-derived exosomal lncRNAs of PaCa patients are novel blood-based biomarkers of disease.

Abstract Long noncoding RNAs (lncRNAs) are RNA molecules with a length greater than 200 nucleotides that do not code for functional proteins. Although, genes play a vital role in immune response against a disease, it is less known that lncRNAs also contribute through gene regulation. Bovine tuberculosis is a significant zoonotic disease caused by Mycobacterium bovis (M. bovis) in cattle. Here, we report the in-silico analysis of the publicly available transcriptomic data of calves infected with M. bovis. A total of 51,812 lncRNAs were extracted across all the samples. A total of 216 genes and 260 lncRNAs were found to be differentially expressed across all the 4 conditions—infected vs uninfected at 8- and 20-week post-infection (WPI), 8 vs 20-WPI of both infected and uninfected. Gene Ontology and Functional annotation showed that 8 DEGs were annotated with immune system GOs and 2 DEGs with REACTOME immune system pathways. Co-expression analysis of DElncRNAs with DEGs revealed the involvement of lncRNAs with the genes annotated with Immune related GOs and pathways. Overall, our study sheds light on the dynamic transcriptomic changes in response to M. bovis infection, particularly highlighting the involvement of lncRNAs with immune-related genes. The identified immune pathways and gene–lncRNA interactions offer valuable insights for further research in understanding host–pathogen interactions and potential avenues for genetic improvement strategies in cattle.

Abstract Background Many long noncoding RNAs (lncRNAs) with altered expression significantly influence colorectal cancer (CRC) progression and behavior. The functions of many lncRNAs in CRC are not clear yet. This study aimed to discover novel lncRNA entities and comprehensively examine and validate their roles and underlying molecular mechanisms in CRC. Methods Tissue samples, both tumourous and non-tumourous, from three CRC patients were submitted for sequencing. Following expression validation in samples from ten patients and four CRC cell lines. The lncRNA KCNMA1-AS2 was synthesized by In-vitro transcription RNA synthesis and the lncRNA was directly transfected into CRC cell lines to overexpress. Functional assays including MTT proliferation assay, Annexin-V/propidium iodide apoptosis assay, wound healing migration assay and cell cycle assays were performed to evaluate the effect of overexpression of KCNMA1-AS2. Furthermore, the binding of KCNMA1-AS2 to miR-1227-5p was confirmed using dual luciferase reporter assays and qPCR analyses. Subsequent bioinformatics analyses identified 58 potential downstream targets of miR-1227-5p across three databases. Results In this study, we identified the lncRNA KCNMA1-AS2, the expression of which was down-regulated consistently in cancer tissues and CRC cell lines compared to non-cancerous tissues. The overexpression of lncRNA KCNMA1-AS2 led to significant reduction in CRC cell proliferation and migration, increase in cell apoptosis, and more cells arrested in S phase. Additionally, the interaction between KCNMA1-AS2 and miR-1227-5p was confirmed through dual luciferase reporter assay and qPCR analysis. It is also putatively predicted that MTHFR and ST8SIA2 may be linked to CRC based on bioinformatics analyses. Conclusions LncRNA KCNMA1-AS2 exhibited distinct gene expression patterns in both CRC tissue and cell lines, impacting various cellular functions while also acting as a sponge for miR-1227-5p.The findings spotlight lncRNA KCNMA1-AS2 as a potential marker for diagnosis and treatment of CRC.

Glioblastoma is the most common primary malignant brain tumor in adults, with a median survival of just over 1 year. The failure of available treatments to achieve remission in patients with glioblastoma (GBM) has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment‐resistant cell repository capable of driving tumor recurrence. In fact, the property of “stemness” itself may be responsible for treatment resistance. In this study, we identify a novel long noncoding RNA (lncRNA), cancer stem cell‐associated distal enhancer of SOX2 (CASCADES), that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in isocitrate dehydrogenase (IDH)‐wild‐type GBM and is significantly enriched in GSCs. Knockdown of CASCADES in GSCs results in differentiation towards a neuronal lineage in a cell‐ and cancer‐specific manner. Bioinformatics analysis reveals that CASCADES functions as a super‐enhancer‐associated lncRNA epigenetic regulator of SOX2. Our findings identify CASCADES as a critical regulator of stemness in GSCs that represents a novel epigenetic and therapeutic target for disrupting the CSC compartment in glioblastoma. [ABSTRACT FROM AUTHOR]

Lipid disorders increase the risk for the development of cardiometabolic disorders, including type 2 diabetes, atherosclerosis, and cardiovascular disease. Lipids levels, apart from diet, smoking, obesity, alcohol consumption, and lack of exercise, are also influenced by genetic factors. Recent studies suggested the role of long noncoding RNAs (lncRNAs) in the regulation of lipid formation and metabolism. Despite their lack of protein-coding capacity, lncRNAs are crucial regulators of various physiological and pathological processes since they affect the transcription and epigenetic chromatin remodelling. LncRNAs act as molecular signal, scaffold, decoy, enhancer, and guide molecules. This review summarises available data concerning the impact of lncRNAs on lipid levels and metabolism, as well as impact on cardiovascular disease risk. This relationship is significant because altered lipid metabolism is a well-known risk factor for cardiovascular diseases, and lncRNAs may play a crucial regulatory role. Understanding these mechanisms could pave the way for new therapeutic strategies to mitigate cardiovascular disease risk through targeted modulation of lncRNAs. The identification of dysregulated lncRNAs may pose promising candidates for therapeutic interventions, since strategies enabling the restoration of their levels could offer an effective means to impede disease progression without disrupting normal biological functions. LncRNAs may also serve as valuable biomarker candidates for various pathological states, including cardiovascular disease. However, still much remains unknown about the functions of most lncRNAs, thus extensive studies are necessary elucidate their roles in physiology, development, and disease. [ABSTRACT FROM AUTHOR]

Medulloblastoma, the most common malignant pediatric brain tumor, is classified into four main molecular subgroups, but group 3 and group 4 tumors are difficult to subclassify and have a poor prognosis. Rapid point-of-care diagnostic and prognostic assays are needed to improve medulloblastoma risk stratification and management. N6-methyladenosine (m6A) is a common RNA modification and long non-coding RNAs (lncRNAs) play a central role in tumor progression, but their impact on gene expression and associated clinical outcomes in medulloblastoma are unknown. Here we analyzed 469 medulloblastoma tumor transcriptomes to identify lncRNAs co-expressed with m6A regulators. Using LASSO-Cox analysis, we identified a five-gene m6A-associated lncRNA signature (M6LSig) significantly associated with overall survival, which was combined in a prognostic clinical nomogram. Using expression of the 67 m6A-associated lncRNAs, a subgroup classification model was generated using the XGBoost machine learning algorithm, which had a classification accuracy > 90%, including for group 3 and 4 samples. All M6LSig genes were significantly correlated with at least one immune cell type abundance in the tumor microenvironment, and the risk score was positively correlated with CD4+ naïve T cell abundance and negatively correlated with follicular helper T cells and eosinophils. Knockdown of key m6A writer genes METTL3 and METTL14 in a group 3 medulloblastoma cell line (D425-Med) decreased cell proliferation and upregulated many M6LSig genes identified in our in silico analysis, suggesting that the signature genes are functional in medulloblastoma. This study highlights a crucial role for m6A-dependent lncRNAs in medulloblastoma prognosis and immune responses and provides the foundation for practical clinical tools that can be rapidly deployed in clinical settings. [ABSTRACT FROM AUTHOR]

Background: Disulfidptosis is an emerging form of cellular death resulting from the binding of intracellular disulfide bonds to actin cytoskeleton proteins. This study aimed to investigate the expression and prognostic significance of hub disulfidptosis-related lncRNAs (DRLRs) in R0 resected hepatocellular carcinoma (HCC) as well as their impact on the malignant behaviour of HCC cells. Methods: A robust signature for R0 resected HCC was constructed using least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression and was validated in an independent internal validation cohort to predict the prognosis of R0 HCC patients. Comprehensive bioinformatics analysis was performed on the hub DRLRs (KDM4A-AS1, MKLN1-AS, and TMCC1-AS1), followed by experimental validation using quantitative real-time polymerase chain reaction (qRT‒PCR) and cellular functional assays. Results: The signature served as an independent prognostic factor applicable to R0 HCC patients across different age groups, tumour stages, and pathological characteristics. Gene Ontology (GO) and gene set enrichment analysis (GSEA) revealed hub pathways associated with this signature. The high-risk group presented an increased abundance of M0 macrophages and activated memory CD4 T cells as well as elevated macrophage and major histocompatibility complex (MHC) class I expression. High-risk R0 HCC patients also presented increased tumour immune dysfunction and exclusion scores (TIDEs), mutation frequencies, and tumour mutational burdens (TMBs). Drug sensitivity analysis revealed that high-risk patients were more responsive to drugs, including GDC0810 and osimertinib. High expression levels of the three hub DRLRs were detected in R0 HCC tissues and HCC cell lines. Functional assays revealed that the three hub DRLRs enhanced HCC cell proliferation, migration, and invasion. Conclusions: A signature was constructed on the basis of three DRLRs, providing novel insights for personalized precision therapy in R0 HCC patients. [ABSTRACT FROM AUTHOR]

To study the degradation of lncRNAs in EPMI in rat brain tissue, this study provides a new direction for the estimation of EPMI. LncRNA high-throughput sequencing was performed on the brain tissues of hemorrhagic shock model rats at 0 h and 24 h, and the target lncRNAs were screened. Samples at 0, 1, 3, 6, 12, 18 and 24 h after death were collected, and miRNA-9 and miRNA-125b were used as reference genes. The relative expression levels of lncRNAs at each PMI were detected by RT–qPCR, and a functional model involving lncRNAs and EPMI was established. Samples were collected at 6, 9, 15, and 21 h after death for functional model verification. The expression of several lncRNAs decreased with the prolongation of EPMI, and the mathematical model established by several lncRNA indices exhibited good fit. The verification results of the multi-index joint function model are significantly better than those of the single-index function model, and the established model is more practical. There is a linear relationship between lncRNAs and EPMI, and the multi-index function model is significantly better than the single-index function model, which is important for EPMI inference in forensic pathology practice. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer (PaCa) is one of the most intractable and fatal malignancies and is associated with the dysregulation of long noncoding RNAs (lncRNAs), which are a large class of noncoding RNAs larger than 200 nt that act as competing endogenous RNAs or sponges for miRNAs to induce tumour biological behaviours. However, their clinical value in treating pancreatic cancer has been poorly explained, but they are essential for improving the prognosis of PaCa patients. Methods: We analysed the plasma-derived exosomal lncRNA profiles of PaCa patients by using whole-transcriptome sequencing analysis and identified significantly differentially expressed lncRNAs, including LINC01268, LINC02802, AC124854.1, and AL132657.1. In the current study, the expression levels of four plasma-derived exosomal lncRNAs in PaCa plasma were validated via quantitative real-time polymerase chain reaction (qRT‒PCR). The relationship between the expression of the four lncRNAs and the clinicopathological features of patients with PaCa was also evaluated. Results: We demonstrated that exosomal LINC01268, LINC02802, AC124854.1 and AL132657.1 were highly expressed in PaCa plasma compared with those in normal controls; moreover, they were positively correlated with the serum expression of carbohydrate antigen 19–9 (CA19-9). The receiver operating characteristic curves (AUCs) of the four lncRNAs were 0.8421, 0.6544, 0.7190, and 0.6321, and the AUC value of the combination of the four exosomal lncRNAs increased to 0.8476, with a sensitivity of 0.72 and specificity of 0.89. These results suggested that the plasma-derived exosomal genes LINC01268, LINC02802, AC124854.1, and AL132657.1 may be novel diagnostic markers for PaCa. Conclusions: Our research demonstrated that the plasma-derived exosomal lncRNAs of PaCa patients are novel blood-based biomarkers of disease. [ABSTRACT FROM AUTHOR]

The clustered homeobox gene family known as the Hox family plays a fundamental role in the morphogenesis of the vertebrate's embryo. A long noncoding RNA (lncRNA), known as HOTTIP (HOXA transcript at the distal tip), has been functionally characterized and contributed to the pathogenesis of various conditions. The current case–control study was undertaken to examine the gene frequencies and shared alleles of the HOTTIP gene in Iranian participants with or without idiopathic recurrent spontaneous abortion (RSA). Both ARMS-PCR reaction and RFLP-PCR techniques were employed to detect three HOTTIP polymorphisms (rs2023843C/T, rs78248039A/T, and rs1859168C/A) in a DNA sample of 161 women with RSA and 177 healthy women. We found that the TT genotype of the HOTTIP rs2023843 C/T polymorphism was associated with a lower risk for idiopathic RSA. In contrast, the TT genotype of the HOTTIP rs78248039 A/T polymorphism was correlated with an enhanced risk of RSA. The presence of the A-allele for HOTTIP rs1859168 C/A polymorphism was associated with an increased risk for idiopathic RSA. Haplotype analysis showed that the T/T/A, C/T/A, T/T/C, and T/A/A haplotypes of rs2023843/rs78248039/rs1859168 enhanced RSA susceptibility. Computational analysis predicted that this lncRNA might act as a potential sponge for some microRNAs; therefore, affecting the expression of genes being targeted by them. In addition, both rs2023843 and rs1859168 variants could alter the local secondary structure of HOTTIP. Our results showed that HOTTIP rs2023843C/T, rs78248039A/T, and rs1859168C/A polymorphisms may confer genetic susceptibility to idiopathic RSA in an Iranian population. [ABSTRACT FROM AUTHOR]

Arteriosclerosis obliterans (ASO) is characterized by arterial narrowing and blockage due to atherosclerosis, influenced by endothelial dysfunction and inflammation. This research focuses on exploring the role of MAGOH-DT, a long noncoding RNA, in mediating endothelial cell dysfunction through endothelial-mesenchymal transition (EndMT) under inflammatory and hyperglycemic stimuli, aiming to uncover potential therapeutic targets for ASO. Differential expression of lncRNAs, including MAGOH-DT, was initially identified in arterial tissues from ASO patients compared to healthy controls through lncRNA microarray analysis. Validation of MAGOH-DT expression in response to tumor necrosis factor-alpha (TNF-α) and high glucose (HG) was performed in human umbilical vein endothelial cells (HUVECs) using RT-qPCR. The effects of MAGOH-DT and HNRPC knockdown on EndMT were assessed by evaluating EndMT markers and TGF-β2 protein expression with Western blot analysis. RNA-immunoprecipitation assays were used to explore the interaction between MAGOH-DT and HNRPC, focusing on their role in regulating TGF-β2 translation. In the results, MAGOH-DT expression is found to be upregulated in ASO and further induced in HUVECs under TNF-α/HG conditions, contributing to the facilitation of EndMT. Silencing MAGOH-DT or HNRPC is shown to inhibit the TNF-α/HG-induced increase in TGF-β2 protein expression, effectively attenuating EndMT processes without altering TGF-β2 mRNA levels. In conclusion, MAGOH-DT is identified as a key mediator in the process of TNF-α/HG-induced EndMT in ASO, offering a promising therapeutic target. Inhibition of MAGOH-DT presents a novel therapeutic strategy for ASO management, especially in cases complicated by diabetes mellitus. Further exploration into the therapeutic implications of MAGOH-DT modulation in ASO treatment is warranted. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) represents a global health concern, ranking as the sixth most common malignancy worldwide and the third leading cause of cancer-related mortality. Despite advances in research, the diagnosis and prognosis of such malignancy remain challenging. Alpha-fetoprotein, the current serum biomarker used in the management of HCC, has limited sensitivity and specificity, making early detection and effective management more difficult. Thus, new management approaches in diagnosis and prognosis are needed to improve the outcome and survival of HCC patients. SNHG1 is a long noncoding RNA mainly expressed in the cell and cytoplasm of cells and is consistently upregulated in tissues and cell lines of HCC, where it acts as an important regulator of various processes: modulation of p53 activity, sponging of microRNAs with consequent upregulation of their target mRNAs, regulation of fatty acid, iron and glucose metabolism, and interaction with immune cells. The deregulation of these processes results in abnormal cell division, angiogenesis, and apoptosis, thus promoting various aspects of tumorigenesis, including proliferation, invasion, and migration of cells. Clinically, a higher expression of SNHG1 predicts poorer clinical outcomes by significantly correlating with bigger, less differentiated, and more aggressive tumors, more advanced disease stages, and lower overall survival in HCC patients. This article comprehensively summarizes the current understanding of the multifaceted roles of SNHG1 in the pathogenesis of HCC, while also highlighting its clinicopathological correlations, therefore concluding that it has potential as a biomarker in HCC diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Aim: Hyperglycemia damages mitochondria and downregulates transcription of mtDNA-encoded genes and the long noncoding RNA LncCytB, causing mitochondrial genomic instability. The genes encoded by mtDNA are transcribed as large polycistronic transcripts, and the 5′ ends of precursor tRNAs are processed by mitochondrial-targeted ribonuclease P (MRPPs). Our aim was to investigate the role of MRPP1 in the downregulation of LncCytB in diabetic retinopathy. Methods: Using human retinal endothelial cells incubated in 20 mM D-glucose for 96 h, the gene expression and mitochondrial localization (immunofluorescence) of MRPP1 and the interaction between MRPP1 and LncCytB (determined by RNA-FISH and RNA immunoprecipitation) were quantified. The results were confirmed in retinal microvessels from streptozotocin-induced diabetic mice and from human donors with documented diabetic retinopathy. Results: Compared to normal glucose, high glucose decreased mRNA and mitochondrial localization of MRPP1 and its interaction with LncCytB. While MRPP1 overexpression prevented glucose-induced decrease in MRPP1–LncCytB interaction, LncCytB expression and mitochondrial damage (reduction in protective nucleoids in mtDNA), MRPP1-siRNA further worsened them. Similar results were obtained from retinal microvessels from diabetic mice and from human donors with diabetic retinopathy. Conclusions: Downregulation of MRPP1 in diabetes suppresses LncCytB transcription, resulting in mitochondrial functional and genomic instability, ultimately leading to the development of diabetic retinopathy. Thus, preventing MRPP1 downregulation has the potential to inhibit retinopathy and prevent the fear of vision loss in diabetic patients. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are RNA molecules with a length greater than 200 nucleotides that do not code for functional proteins. Although, genes play a vital role in immune response against a disease, it is less known that lncRNAs also contribute through gene regulation. Bovine tuberculosis is a significant zoonotic disease caused by Mycobacterium bovis (M. bovis) in cattle. Here, we report the in-silico analysis of the publicly available transcriptomic data of calves infected with M. bovis. A total of 51,812 lncRNAs were extracted across all the samples. A total of 216 genes and 260 lncRNAs were found to be differentially expressed across all the 4 conditions—infected vs uninfected at 8- and 20-week post-infection (WPI), 8 vs 20-WPI of both infected and uninfected. Gene Ontology and Functional annotation showed that 8 DEGs were annotated with immune system GOs and 2 DEGs with REACTOME immune system pathways. Co-expression analysis of DElncRNAs with DEGs revealed the involvement of lncRNAs with the genes annotated with Immune related GOs and pathways. Overall, our study sheds light on the dynamic transcriptomic changes in response to M. bovis infection, particularly highlighting the involvement of lncRNAs with immune-related genes. The identified immune pathways and gene–lncRNA interactions offer valuable insights for further research in understanding host–pathogen interactions and potential avenues for genetic improvement strategies in cattle. [ABSTRACT FROM AUTHOR]

Recently, substantial evidence has demonstrated that pseudogene-derived long noncoding RNAs (lncRNAs) as regulatory RNAs have been implicated in basic physiological processes and disease development through multiple modes of functional interaction with DNA, RNA, and proteins. Here, we report an important role for GBP1P1, the pseudogene of guanylate-binding protein 1, in regulating influenza A virus (IAV) replication in A549 cells. GBP1P1 was dramatically upregulated after IAV infection, which is controlled by JAK/STAT signaling. Functionally, ectopic expression of GBP1P1 in A549 cells resulted in significant suppression of IAV replication. Conversely, silencing GBP1P1 facilitated IAV replication and virus production, suggesting that GBP1P1 is one of the interferon-inducible antiviral effectors. Mechanistically, GBP1P1 is localized in the cytoplasm and functions as a sponge to trap DHX9 (DExH-box helicase 9), which subsequently restricts IAV replication. Together, these studies demonstrate that GBP1P1 plays an important role in antagonizing IAV replication. IMPORTANCE Long noncoding RNAs (lncRNAs) are extensively expressed in mammalian cells and play a crucial role as regulators in various biological processes. A growing body of evidence suggests that host-encoded lncRNAs are important regulators involved in host–virus interactions. Here, we define a novel function of GBP1P1 as a decoy to compete with viral mRNAs for DHX9 binding. We demonstrate that GBP1P1 induction by IAV is mediated by JAK/STAT activation. In addition, GBP1P1 has the ability to inhibit IAV replication. Importantly, we reveal that GBP1P1 acts as a decoy to bind and titrate DHX9 away from viral mRNAs, thereby attenuating virus production. This study provides new insight into the role of a previously uncharacterized GBP1P1, a pseudogene-derived lncRNA, in the host antiviral process and a further understanding of the complex GBP network. [ABSTRACT FROM AUTHOR]

Long non‐coding RNA RP11‐64B16.4 (myocardial infarction protection‐related lncRNA [MIPRL]) is among the most abundant and the most upregulated lncRNAs in ischemic human hearts. However, its role in ischemic heart disease is unknown. We found MIPRL was conserved between human and mouse and its expression was increased in mouse hearts after acute myocardial infarction (AMI) and in cultured human and mouse cardiomyocytes after hypoxia. The infarcted size, cardiac cell apoptosis, cardiac dysfunction, and cardiac fibrosis were aggravated in MIPRL knockout mice after AMI. The above adverse results could be reversed by re‐expression of MIPRL via adenovirus expressing MIPRL. Both in vitro and in vivo, we identified that heat shock protein beta‐8 (HSPB8) was a target gene of MIPRL, which was involved in MIPRL‐mediated anti‐apoptotic effects on cardiomyocytes. We further discovered that MIPRL could combine with the messenger RNA (mRNA) of HSPB8 and increase its expression in cardiomyocytes by enhancing the stability of HSPB8 mRNA. In summary, we have found for the first time that the ischemia‐enhanced lncRNA MIPRL protects against AMI via its target gene HSPB8. MIPRL might be a novel promising therapeutic target for ischemic heart diseases such as AMI. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum, the human malaria parasite, infects two hosts and various cell types, inducing distinct morphological and physiological changes in the parasite in response to different environmental conditions. These variations required the parasite to adapt and develop elaborate molecular mechanisms to ensure its spread and transmission. Recent findings have significantly improved our understanding of the regulation of gene expression in P. falciparum. Here, we provide an up-to-date overview of technologies used to highlight the transcriptomic adjustments occurring in the parasite throughout its life cycle. We also emphasize the complementary and complex epigenetic mechanisms regulating gene expression in malaria parasites. This review concludes with an outlook on the chromatin architecture, the remodeling systems, and how this 3D genome organization is critical in various biological processes.

Abstract Progression of diabetic retinopathy resists arrest even after institution of intensive glycemic control, suggesting a “metabolic memory” phenomenon, but the mechanism responsible for this phenomenon is still elusive. Gene expression and biological processes can also be regulated by long noncoding RNAs (LncRNAs), the RNAs with >200 nucleotides and no open reading frame for translation, and several LncRNAs are aberrantly expressed in diabetes. Our aim was to identify retinal LncRNAs that fail to reverse after termination of hyperglycemia. Microarray analysis was performed on retinal RNA from streptozotocin‐induced diabetic rats in poor glycemic control for 8 months, followed by in good glycemic control (blood glucose >400 mg/dL), or for 4 months, with four additional months of good glycemic control (blood glucose 1479 differentially expressed LncRNAs (710 downregulated, 769 upregulated), and among those, 511 common LncRNAs had similar expression in Diab and Rev groups (139 downregulated, 372 upregulated). Gene Ontology/pathway analysis identified limited LncRNAs in biological processes, but analysis based on biological processes/molecular function revealed >350 genes with similar expression in Diab and Rev groups; these genes were mainly associated with stress response, cell death, mitochondrial damage and cytokine production. Thus, identifying retinal LncRNAs and their gene targets that do not benefit from termination of hyperglycemia have potential to serve as therapeutic targets to slow down the progression of diabetic retinopathy.

Prostate cancer is a malignant tumor caused by the malignant proliferation of epithelial cells, which is highly heterogeneous and drug-resistant, and neuroendocrine prostate cancer (NEPC) is an essential cause of drug resistance in its late stage. Elucidating the evolution of NEPC and the resistance process of enzalutamide, a novel antiandrogen, will be of great help in improving the prognosis of patients. As a research hotspot in the field of molecular biology in recent years, the wide range of biological functions of long noncoding RNAs (lncRNAs) has demonstrated their position in the therapeutic process of many diseases, and a large number of studies have revealed their critical roles in tumor progression and drug resistance. Therefore, elucidating the involvement of lncRNAs in the formation of NEPCs and their interrelationship with enzalutamide resistance may provide new ideas for a deeper understanding of the development of this disease and the occurrence of enzalutamide resistance and give a new direction for reversing the therapeutic dilemma of advanced prostate cancer. This article focuses on lncRNAs that regulate enzalutamide resistance and the neuroendocrine transition of prostate cancer through epigenetic, androgen receptor (AR) signaling, and non-AR pathways that act as “molecular sponges” interacting with miRNAs. Some insights into these mechanisms are used to provide some help for subsequent research in this area.

Abstract Cholangiocarcinoma (CCA) was identified as a malignant tumor with rising incidence and mortality rates, and the roles of long noncoding RNA (lncRNA) in CCA remained not entirely clear. In this study, LINC00511 had high expression in CCA, which was closely related to poor prognosis. Knockdown of LINC00511 significantly inhibited cell malignant biological behaviors. It also affected the stemness of CCA, evidenced by decreased SOX2 protein expression. Moreover, the study revealed the interaction of LINC00511, YTHDF2, and SOX2 in CCA. Specifically, LINC00511 facilitated the formation of a complex with YTHDF2 on SOX2 mRNA, which uniquely enhances the mRNA's stability through m6A methylation sites. This stabilization appears crucial for maintaining malignant behaviors in CCA cells. Additionally, LINC00511 modulated SOX2 expression via the PI3K/AKT signaling pathway. Meanwhile, SOX2 can also promote LINC00511 expression as an upstream transcription factor, thereby confirming a positive feedback loop formed by LINC00511, YTHDF2, and SOX2, which plays a significant role in the occurrence and development of CCA. Finally, the study successfully constructed two patient‐derived xenograft models, revealing the vital role of LINC00511 in CCA development. In summary, this research provides a comprehensive understanding of the role of LINC00511 in the pathogenesis of CCA.

Long noncoding RNA (lncRNA) genes outnumber protein coding genes in the human genome and the majority remain uncharacterized. A major difficulty in generalizing understanding of lncRNA function is the dearth of gross sequence conservation, both for lncRNAs across species and for lncRNAs that perform similar functions within a species. Machine learning based methods which harness vast amounts of information on RNAs are increasingly used to impute certain biological characteristics. This includes interactions with proteins that are important mediators of RNA function, thus enabling the generation of knowledge in contexts for which experimental data are lacking. Here, we applied a natural language-based machine learning approach that enabled us to identify RNA binding protein interactions in lncRNA transcripts, using only RNA sequence as an input. We found that this predictive method is a powerful approach to infer conserved binding across species as distant as human and opossum, even in the absence of sequence conservation, thus informing on sequence-function relationships for these poorly understood RNAs.

Objective: Emerging evidence highlights the pivotal roles of long non-coding RNAs (lncRNAs) in lipid metabolism. Apoprotein C3 (ApoC3) is a well-established therapeutic target for hypertriglyceridemia and exhibits a strong association with cardiovascular disease. However, the exact mechanisms via which the lncRNAs control ApoC3 expression remain unclear. Methods: We identified a novel long noncoding RNA (lncRNA), GM47544, within the ApoA1/C3/A4/A5 gene cluster. Subsequently, the effect of GM47544 on intracellular triglyceride metabolism was analyzed. The diet-induced mouse models of hyperlipidemia and atherosclerosis were established to explore the effect of GM47544 on dyslipidemia and plaque formation in vivo. The molecular mechanism was explored through RNA sequencing, immunoprecipitation, RNA pull-down assay, and RNA immunoprecipitation. Results: GM47544 was overexpressed under high-fat stimulation. GM47544 effectively improved hepatic steatosis, reduced blood lipid levels, and alleviated atherosclerosis in vitro and in vivo. Mechanistically, GM47544 directly bound to ApoC3 and facilitated the ubiquitination at lysine 79 in ApoC3, thereby facilitating ApoC3 degradation via the ubiquitin-proteasome pathway. Moreover, we identified AP006216.5 as the human GM47544 transcript, which fulfills a comparable function in human hepatocytes. Conclusions: The identification of GM47544 as a lncRNA modulator of ApoC3 reveals a novel mechanism of post-translational modification, with significant clinical implications for the treatment of hypertriglyceridemia and atherosclerosis.

The ATR-Chk1 pathway is essential in cellular responses to DNA damage and replication stress, whereas the role of long noncoding RNAs (lncRNAs) in regulating this pathway remains largely unknown. In this study, we identify an ATR and Chk1 interacting lncRNA (ACIL, also known as LRRC75A-AS1 or SNHG29), which promotes the phosphorylation of Chk1 by ATR upon DNA damages. High ACIL levels are associated with chemoresistance to DNA damaging agents and poor outcome of breast cancer patients. ACIL knockdown sensitizes breast cancer cells to DNA damaging drugs in vitro and in vivo. ACIL protects cancer cells against DNA damages by inducing cell cycle arrest, stabilizing replication forks and inhibiting unscheduled origin firing, thereby guarding against replication catastrophe and contributing to DNA damage repair. These findings demonstrate a lncRNA-dependent mechanism of activating the ATR-Chk1 pathway and highlight the potential of utilizing ACIL as a predictive biomarker for chemotherapy sensitivity, as well as targeting ACIL to reverse chemoresistance in breast cancer.

Qianhui Zhou,1 Yi Liu,1 Yan Gao,1 Lingli Quan,1 Lin Wang,1 Hao Wang2 1Department of Respiratory and Critical Care Medicine, Zhuzhou Central Hospital, Zhuzhou, 412000, People’s Republic of China; 2Department of Urology, The First Affiliated Hospital, Hengyang Medical School, University of South China, HengYang, Hunan, 421005, People’s Republic of ChinaCorrespondence: Hao Wang, Email wanghao872013@163.comBackground: Lung cancer is the leading cause of cancer deaths worldwide, primarily due to lung adenocarcinoma (LUAD). However, the heterogeneity of programmed cell death results in varied prognostic and predictive outcomes. This study aimed to develop an LUAD evaluation marker based on cuproptosis-related lncRNAs.Methods: First, transcriptome data and clinical data related to LUAD were downloaded from the Cancer Genome Atlas (TCGA), and cuproptosis-related genes were analyzed to identify cuproptosis-related lncRNAs. Univariate, LASSO, and multivariate Cox regression analyses were conducted to construct cuproptosis-associated lncRNA models. LUAD patients were categorized into high-risk and low-risk groups using prognostic risk values. Kaplan-Meier analysis, PCA, GSEA, and nomograms were employed to evaluate and validate the results.Results: 7 cuproptosis-related lncRNAs were identified, and a risk model was created. High-risk tumors exhibited cuproptosis-related gene alterations in 95.54% of cases, while low-risk tumors showed alterations in 85.65% of cases, mainly involving TP53. The risk value outperformed other clinical variables and tumor mutation burden as a predictor of 1-, 3-, and 5-year overall survival. The cuproptosis-related lncRNA-based risk model demonstrated high validity for LUAD evaluation, potentially influencing individualized treatment approaches. Expression analysis of four candidate cuproptosis-related lncRNAs (AL606834.1, AL161431.1, AC007613.1, and LINC02835) in LUAD tissues and adjacent normal tissues revealed significantly higher expression levels of AL606834.1 and AL161431.1 in LUAD tissues, positively correlating with tumor stage, lymph node metastasis, and histopathological grade. Conversely, AC007613.1 and LINC02835 exhibited lower expression levels, negatively correlating with these factors. High expression of AL606834.1 and AL161431.1 indicated poor prognosis, while low expression of AC007613.1 and LINC02835 was associated with unfavorable outcomes. Univariate and multivariate analyses confirmed these lncRNAs as independent risk factors for LUAD prognosis.Conclusion: The 4 cuproptosis-related (lncRNAsAL606834.1, AL161431.1, AC007613.1, and LINC02835) can accurately predict the prognosis of patients with LUAD and may provide new insights into clinical applications and immunotherapy.Keywords: lung adenocarcinoma, tumor mutation load, cuproptosis, long noncoding RNA, immunotherapeutic response

Abstract Objective To identify differentially expressed long noncoding RNAs (lncRNAs) in condyloma acuminatum (CA) and to explore their probable regulatory mechanisms by establishing coexpression networks. Methods High-throughput RNA sequencing was performed to assess genome-wide lncRNA expression in CA and paired adjacent mucosal tissue. The expression of candidate lncRNAs and their target genes in larger CA specimens was validated using real-time quantitative reverse transcriptase polymerase chain reaction (RT‒qPCR). Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used for the functional enrichment analysis of these candidate lncRNAs and differential mRNAs. The coexpressed mRNAs of the candidate lncRNAs, calculated by Pearson’s correlation coefficient, were also analysed using GO and KEGG analysis. In addition, the interactions among differentially expressed lncRNAs (DElncRNAs)-cis-regulatory transcription factors (cisTFs)-differentially expressed genes (DEGs) were analysed and their network was constructed. Results A total of 546 lncRNAs and 2553 mRNAs were found to be differentially expressed in CA compared to the paired control. Functional enrichment analysis revealed that the DEGs coexpressed with DElncRNAs were enriched in the terms of cell adhesion and keratinocyte differentiation, and the pathways of ECM-receptor interaction, local adhesion, PI3K/AKT and TGF-ß signaling. We further constructed the network among DElncRNAs-cisTFs-DEGs and found that these 95 DEGs were mainly enriched in GO terms of epithelial development, regulation of transcription or gene expression. Furthermore, the expression of 3 pairs of DElncRNAs and cisTFs, EVX1-AS and HOXA13, HOXA11-AS and EVX1, and DLX6-AS and DLX5, was validated with a larger number of specimens using RT‒qPCR. Conclusion CA has a specific lncRNA profile, and the differentially expressed lncRNAs play regulatory roles in mRNA expression through cis-acting TFs, which provides insight into their regulatory networks. It will be useful to understand the pathogenesis of CA to provide new directions for the prevention, clinical treatment and efficacy evaluation of CA.

Abstract Zinc finger antisense 1 (ZFAS1), a newly discovered long noncoding RNA, is expressed in various tissues and organs and has been introduced an oncogenic gene in human malignancies. In various cancers, ZFAS1 regulates apoptosis, cell proliferation, the cell cycle, migration, translation, rRNA processing, and spliceosomal snRNP assembly; targets signaling cascades; and interacts with transcription factors via binding to key proteins and miRNAs, with conflicting findings on its effect on these processes. ZFAS1 is elevated in different types of cancer, like colorectal, colon, osteosarcoma, and gastric cancer. Considering the ZFAS1 expression pattern, it also has the potential to be a diagnostic or prognostic marker in various cancers. The current review discusses the mode of action of ZFAS1 in various human cancers and its regulation function related to chemoresistance comprehensively, as well as the potential role of ZFAS1 as an effective and noninvasive cancer-specific biomarker in tumor diagnosis, prognosis, and treatment. We expected that the current review could fill the current scientific gaps in the ZFAS1-related cancer causative mechanisms and improve available biomarkers.

Abstract Cancer remains a leading cause of mortality and poses a substantial threat to public health. Studies have revealed that Long noncoding RNA DANCR is a cytoplasmic lncRNA whose aberrant expression plays a pivotal role in various cancer types. Within tumour biology, DANCR exerts regulatory control over crucial processes such as proliferation, invasion, metastasis, angiogenesis, inflammatory responses, cellular energy metabolism reprogramming, and apoptosis. By acting as a competitive endogenous RNA for miRNAs and by interacting with proteins and mRNAs at the molecular level, DANCR contributes significantly to cancer progression. Elevated DANCR levels have also been linked to heightened resistance to anticancer drugs. Moreover, the detection of circulating DANCR holds promise as a valuable biomarker for aiding in the clinical differentiation of different cancer types. This article offers a comprehensive review and elucidation of the primary functions and molecular mechanisms through which DANCR influences tumours.

Abstract Purpose Multiple myeloma (MM) is the second most common hematologic malignancy, and there is no cure for this disease. This study aimed to explore the prognostic value of long noncoding RNAs (lncRNAs) in MM and to reveal related immune and chemotherapy resistance mechanisms. Methods In this study, lncRNA profiles from the Multiple Myeloma Research Foundation (MMRF) and Gene Expression Omnibus (GEO) databases were analyzed to identify lncRNAs linked to MM patient survival. A risk assessment model stratified patients into high- and low-risk groups, and survival was evaluated. Additionally, a triple-ceRNA (lncRNA–miRNA–mRNA) network was constructed, and functional analysis was performed. The research also involved immune function analysis and chemotherapy drug sensitivity assessment using oncoPredict and the GDSC dataset. Results We identified 422 lncRNAs significantly associated with overall survival in MM patients and ultimately focused on the 6 with the highest prognostic value. These lncRNAs were used to develop a risk score formula that stratified patients into high- and low-risk groups. Kaplan–Meier analysis revealed shorter survival in high-risk patients. We integrated this lncRNA signature with clinical parameters to construct a nomogram for predicting MM prognosis. Additionally, a triple-ceRNA network was constructed to reveal potential miRNA targets, coding genes related to these lncRNAs and significantly enriched pathways. Immune checkpoint gene expression and immune cell composition were also analyzed in relation to the lncRNA risk score. Finally, using the oncoPredict tool, we observed that high-risk patients exhibited decreased sensitivity to key MM chemotherapeutics, suggesting that lncRNA profiles are linked to chemotherapy resistance.

Polycystic ovary syndrome (PCOS) is the most common condition affecting women of reproductive age globally. PCOS continues to be the largest contributing factor to female infertility despite significant progress in our knowledge of the molecular underpinnings and treatment of the condition. The fact that PCOS is a very diverse condition makes it one of the key reasons why we haven't been able to overcome it. Non-coding RNAs (ncRNAs) are implicated in the development of PCOS, according to growing evidence. However, it is unclear how the complex regulatory relationships between the many ncRNA types contribute to the growth of this malignancy. Competing endogenous RNA (ceRNA), a recently identified mechanism in the RNA world, suggests regulatory interactions between various RNAs, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), transcribed pseudogenes, and circular RNAs (circRNAs). Recent studies on PCOS have shown that dysregulation of multiple ceRNA networks (ceRNETs) between these ncRNAs plays crucial roles in developing the defining characteristics of PCOS development. And it is believed that such a finding may open a new door for a deeper comprehension of PCOS's unexplored facets. In addition, it may be able to provide fresh biomarkers and effective therapy targets for PCOS. This review will go over the body of information that exists about the primary roles of ceRNETs before highlighting the developing involvement of several newly found ceRNETs in a number of PCOS characteristics.

Background and purpose: Long noncoding RNA (lncRNA) can regulate gene transcription, mRNA shear, stabilization and translation, and it is an important regulatory factor in a variety of biological processes. This study aimed to investigate the expression and clinical features of lncRNA FLJ30679 in oral squamous cell carcinoma (OSCC) and its effect on the malignant biological behavior of OSCC. Methods: The expression of FLJ30679 in head and neck squamous cell carcinoma (HNSCC) tissues and normal tissues was analyzed by the UCSC Xena database for expression and prognosis. The expression of FLJ30679 in OSCC cell lines was detected by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR). The subcellular localization of FLJ30679 in OSCC cells was detected by RNA nuclear-cytoplasmic fractionation assays. FLJ30679 Smart Silencer was used to establish the FLJ30679 knockdown group (SS-FLJ30679), and overexpression plasmid of FLJ30679 was used to establish FLJ30679 overexpression group (FLJ30679). The effects of altered FLJ30679 expression on the proliferative and migration capacity of OSCC cells were examined by cell counting kit-8 (CCK-8) and transwell migration assays. RTFQ-PCR and Western blot were used to determine the effect of altered FLJ30679 expression on the expression of epithelial-mesenchymal transition (EMT)-related genes in OSCC cells. The effects of altered FLJ30679 expression on the phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway were detected by Western blot. Results: Online query of database showed that FLJ30679 expression was higher in HNSCC tissues compared to normal tissues (P

Abstract Background PCD-related long non-coding RNAs (PRLs) are rarely investigated in relation to clear cell renal carcinoma (ccRCC). As part of this study, we evaluated the immunological potential of PRL signatures as a biomarker for ccRCC prognosis and immunological function. Materials and methods Data were downloaded from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) databases. A Pearson correlation analysis was conducted on the 27 PCD-associated genes to determine whether lncRNAs were significantly associated with PCD. Kaplan–Meier analysis, biological function identification, immune infiltration analysis, estimation of efficacy of immunotherapy and targeted drug screening, and exploration of the landscape of mutation status were conducted by analyzing the risk scores. Results Seven PRLs, LINC02747, AP001636.3, AC022126.1, LINC02657, LINC02609, LINC02154, and ZNNT1, were used to divide patients with ccRCC into groups with high and low risk. High-risk patients had a worse prognosis than low-risk patients, according to the results, and the PRL signature showed promising predictive ability. More immune cells were clustered in the high-risk group, whereas the immune cell function of the low-risk group was significantly suppressed. The high-risk group was less sensitive to immunotherapy, whereas the low-risk group had positive responses to most drugs. Conclusions Collectively, we established and verified a PRL signature that could competently guide the prognostic survival and immunotherapy of ccRCC. In addition, molecular subtypes were determined for ccRCC based on PRL expression, which may help elucidate the underlying molecular mechanism of ccRCC and develop targeted treatments.

Abstract Background Long noncoding RNAs (lncRNAs) have surpassed the number of protein-coding genes, yet the majority have no known function. We previously discovered 844 lncRNAs that were genetically linked to breast cancer through genome-wide association studies (GWAS). Here, we show that a subset of these lncRNAs alter breast cancer risk by modulating cell proliferation, and provide evidence that a reduced expression on one lncRNA increases breast cancer risk through aberrant DNA replication and repair. Methods We performed pooled CRISPR-Cas13d-based knockdown screens in breast cells to identify which of the 844 breast cancer-associated lncRNAs alter cell proliferation. We selected one of the lncRNAs that increased cell proliferation, KILR, for follow-up functional studies. KILR pull-down followed by mass spectrometry was used to identify binding proteins. Knockdown and overexpression studies were performed to assess the mechanism by which KILR regulates proliferation. Results We show that KILR functions as a tumor suppressor, safeguarding breast cells against uncontrolled proliferation. The half-life of KILR is significantly reduced by the risk haplotype, revealing an alternative mechanism by which variants alter cancer risk. Mechanistically, KILR sequesters RPA1, a subunit of the RPA complex required for DNA replication and repair. Reduced KILR expression promotes breast cancer cell proliferation by increasing the available pool of RPA1 and speed of DNA replication. Conversely, KILR overexpression promotes apoptosis in breast cancer cells, but not normal breast cells. Conclusions Our results confirm lncRNAs as mediators of breast cancer risk, emphasize the need to annotate noncoding transcripts in relevant cell types when investigating GWAS variants and provide a scalable platform for mapping phenotypes associated with lncRNAs.