Small Nucleolar RNA Host Gene Research Articles

Small nucleolar RNA host gene 5 plays a role in orthodontic tooth movement by inhibiting osteoclast differentiation.

The alveolar bone remodelling promoted by reasonable mechanical force triggers orthodontic tooth movement (OTM). The generation of osteoclasts is essential in this process. However, the mechanism of mechanical force mediating osteoclast differentiation remains elusive. Small nucleolar RNA host gene 5 (SNHG5), which was reported to mediate the osteogenic differentiation of bone marrow mesenchymal stem cells in our previous study, was downregulated in human periodontal ligament cells (hPDLCs) under mechanical force. At the same time, the RANKL/OPG ratio increased. Based on this, we probed into the role of SNHG5 in osteoclast formation during OTM and the relevant mechanism. SNHG5 and the RANKL/OPG ratio under different compressive forces were detected by western blotting (WB) and qRT-PCR. Impact of overexpression or knockdown of SNHG5 on osteoclast differentiation was detected by qRT-PCR, WB and transwell experiments. The combination of SNHG5 and C/EBPβ was verified by RNA immunoprecipitation and RNA pull-down assays. The expression of SNHG5 and osteoclast markers in gingiva were analysed by qRT-PCR and the paraffin sections of periodontal tissues were used for histological analysis. Compressive force downregulated SNHG5 and upregulated the RANKL/OPG ratio in hPDLCs. Overexpression of SNHG5 inhibited RANKL's expression and osteoclast differentiation. SNHG5 combined with C/EBPβ, a regulator of osteoclast. The expression of SNHG5 in periodontal tissue decreased during OTM. SNHG5 inhibited osteoclast differentiation during OTM, achieved by affecting RANKL secretion, which may provide a new idea to interfere with bone resorption during orthodontic treatment.

SNHG1 knockdown promotes osteogenic differentiation of hDFSCs through anti-oxidative stress mediated by autophagy.

The long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) plays a crucial role in tumorigenesis and is frequently employed as a prognostic biomarker. However, its involvement in the osteogenic differentiation of oral stem cells, particularly human dental follicle stem cells (hDFSCs), remains unclear. Our investigation revealed that the absence of SNHG1 enhances the osteogenic differentiation of hDFSCs. Furthermore, the downregulation of SNHG1 induces autophagy in hDFSCs, leading to a reduction in intracellular oxidative stress levels. Notably, this effect is orchestrated through the epigenetic regulation of EZH2. Our study unveils a novel function of SNHG1 in governing the osteogenic differentiation of hDFSCs, offering fresh insights for an in-depth exploration of the molecular mechanisms underlying dental follicle development. These findings not only provide a foundation for advancing the understanding of SNHG1 but also present innovative perspectives for promoting the repair and regeneration of periodontal supporting tissue, ultimately contributing to the restoration of periodontal health and tooth function.

The potential role of SNHG16/ miRNA-146a/ TRAF6 signaling pathway in the protective effect of zoledronate against colorectal cancer and associated osteoporosis in mouse model

Bone fracture as a consequence of colorectal cancer (CRC) and associated osteoporosis (OP) is considered a risk factor for increasing the mortality rate among CRC patients. SNHG16/ miRNA-146a/ TRAF6 signaling pathway is a substantial contributor to neoplastic evolution, progression, and metastasis. Here, we investigated the effect of zoledronate (ZOL) on the growth of CRC and associated OP in a mouse model. Thirty Balb/c mice were divided into Naïve, azoxymethane (AOM)/dextran sodium sulfate (DSS), and ZOL groups. Body weight and small nucleolar RNA host gene 16 (SNHG16) expression, microRNA-146a, and TRAF6 in bone, colon, and stool were investigated. Samples of colon and bone were collected and processed for light microscopic, immunohistochemical staining for cytokeratin 20 (CK20), nuclear protein Ki67 (pKi-67), and caudal type homeobox transcription factor 2 (CDx2) in colon and receptor activator of nuclear factor kB (RANK) and osteoprotegerin (OPG) in bone. A computerized tomography (CT) scan of the femur and tibia was studied. ZOL produced a significant decrease in the expression of SNHG16 and TRAF6 and an increase in miRNA-146a in the colon and bone. ZOL administration improved the histopathological changes in the colon, produced a significant decrease in CK20 and Ki-67, and increased CDx2 expressions. In bone, ZOL prevented osteoporotic changes and tumour cell invasion produced a significant decrease in RANK and an increase in OPG expressions, alongside improved bone mineral density in CT scans. ZOL could be a promising preventive therapy against colitis-induced cancer and associated OP via modulation expression of SNHG16, miRNA-146a, and TRAF6.

Decoding the neurotoxic effects of propofol: insights into the RARα-Snhg1-Bdnf regulatory cascade.

The potential neurotoxic effects of propofol, an extensively utilized anesthetic, underline the urgency to comprehend its influence on neuronal health. Insights into the role of the retinoic acid receptor-α, small nucleolar RNA host gene 1, and brain-derived neurotrophic factor (RARα-Snhg1-Bdnf) network can offer significant advancements in minimizing these effects. The study targets the exploration of the RARα and Snhg1 regulatory network's influence on Bdnf expression in the realm of propofol-induced neurotoxicity. Harnessing the Gene Expression Omnibus (GEO) database and utilizing JASPAR and RNA-Protein Interaction Prediction (RPISeq) database for projections, the study embarks on an in-depth analysis employing both in vitro and in vivo models. The findings draw a clear link between propofol-induced neurotoxicity and the amplification of RAR signaling pathways, impacting hippocampal development and apoptosis and leading to increased RARα and Snhg1 and decreased Bdnf. Propofol is inferred to accentuate neurotoxicity by heightening RARα and Snhg1 interactions, culminating in Bdnf suppression.NEW & NOTEWORTHY This study aimed to decode propofol's neurotoxic effects on the regulatory cascade, provide insights into the RARα-Snhg1-Bdnf interaction, apply extensive validation techniques, provide a detailed analysis and exploration of propofol's neurotoxicity, and offer a comprehensive approach to understanding molecular interactions.

Long noncoding RNA small nucleolar RNA host genes as prognostic molecular biomarkers in hepatocellular carcinoma: A meta-analysis.

Recently, increasing data have suggested that the lncRNA small nucleolar RNA host genes (SNHGs) were aberrantly expressed in hepatocellular carcinoma (HCC), but the association between the prognosis of HCC and their expression remained unclear. The purpose of this meta-analysis was to determine the prognostic significance of lncRNA SNHGs in HCC. We systematically searched Embase, Web of Science, PubMed, and Cochrane Library for eligible articles published up to February 2024. The prognostic significance of SNHGs in HCC was evaluated by hazard ratios (HRs) and 95% confidence intervals (CIs). Odds ratios (ORs) were used to assess the clinicopathological features of SNHGs. This analysis comprised a total of 25 studies covering 2314 patients with HCC. The findings demonstrated that over-expressed SNHGs were associated with larger tumor size, multiple tumor numbers, poor histologic grade, earlier lymphatic metastasis, vein invasion, advanced tumor stage, portal vein tumor thrombosis (PVTT), and higher alpha-fetoprotein (AFP) level, but not with hepatitis B virus (HBV) infection, and cirrhosis. In terms of prognosis, patients with higher SNHG expression were more likely to have shorter overall survival (OS), relapse-free survival (RFS), and disease-free survival (DFS). In conclusion, upregulation of SNHGs expression correlates with shorter OS, RFS, DFS, tumor size and numbers, histologic grade, lymphatic metastasis, vein invasion, tumor stage, PVTT, and AFP level, suggesting that SNHGs may serve as prognostic biomarkers in HCC.

Small nucleolar RNA host gene 1 silence inhibits the lipopolysaccharide-induced microglial apoptosis and inflammation.

Microglia activation is an early mediator of neuroinflammation and a major contributor to spinal damage and motor dysfunction. This study was designed to investigate the role of small nucleolar RNA host gene 1 (SNHG1) on the apoptosis and inflammatory response of microglial cell BV-2 and its underlying molecular mechanism. The C5 lamina contusion-induced mouse model of spinal cord injury (SCI) was constructed. Mouse microglia BV2 was stimulated by lipopolysaccharide (LPS) to establish the in vitro model of SCI. The quantitative reverse transcription polymerase chain reaction method was used to quantify RNA expression levels. Enzyme-linked immunosorbent assays were used to quantify concentrations of inflammatory cytokines. Protein levels were assessed by western blotting, and apoptosis was assessed by flow cytometry. Dual luciferase reporter gene assay and RNA pull-down assay were conducted to investigate the binding relationships between molecules. Upregulation of SNHG1 and downregulation of miR-195-5p were observed in the spinal cords of SCI mouse model. LPS treatment led to elevation of SNHG1 expression in BV2 cells, as well as accelerated apoptosis and inflammation. Evident mitigation of LPS-induced BV2 cell damage was observed after SNHG1 knockdown. MiR-195-5p was identified as a target of SNHG1. Inhibition of miR-195-5p restored the impact of SNHG1 knockdown on cell damage of LPS-treated BV2 cells. Furthermore, miR-195-5p can target activating transcription factor-6 (ATF6). In summary, SNHG1 knockdown ameliorates LPS-induced microglial apoptosis and inflammatory response via the miR-195-5p/ATF6 axis, providing a novel direction for SCI treatment.

Mechanisms underlying LncRNA SNHG1 regulation of Alzheimer’s disease involve DNA methylation

ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disease associated with long non-coding RNAs and DNA methylation; however, the mechanisms underlying the role of lncRNA small nucleolar RNA host gene 1 (lncRNA SNHG1) and subsequent involvement of DNA methylation in AD development are not known. The aim of this study was to examine the regulatory mechanisms attributed to lncRNA SNHG1 gene utilizing 2 strains of senescence-accelerated mouse prone 8 (SAMP8) model of AD and compared to senescence-accelerated mouse resistant (SAMR) considered a control. Both strains of the mouse were transfected with either blank virus, psLenti-U6-SNHG1(low gene expression) virus, and psLenti-pA-SNHG1(gene overexpression) virus via a single injection into the brains for 2 weeks. At 2 weeks mice were subjected to a Morris water maze to determine any behavioral effects followed by sacrifice to extract hippocampal tissue for Western blotting to measure protein expression of p-tau, DNMT1, DNMT3A, DNMT3B, TET1, and p-Akt. No marked alterations were noted in any parameters following blank virus transfection. In SAMP8 mice, a significant decrease was noted in protein expression of DNMT1, DNMT3A, DNMT3B, and p-Akt associated with rise in p-tau and TET1. Transfection with ps-Lenti-U6-SNHG1 alone in SAMR1 mice resulted in a significant rise in DNMTs and p-Akt and a fall in p-tau and TET1. Transfection of SAMP8 with ps-Lenti-U6-SNHG1 blocked effects on overexpression noted in this mouse strain. However, knockdown of lncRNA SNHG1 yielded the opposite results as found in SAMR1 mice. In conclusion, the knockdown of lncRNA SNHG1 enhanced DNA methylation through the PI3K/Akt signaling pathway, thereby reducing the phosphorylation levels of tau in SAMP8 AD model mice with ameliorating brain damage attributed to p-tau accumulation with consequent neuroprotection.

LncRNA SNHG26 promotes gastric cancer progression and metastasis by inducing c-Myc protein translation and an energy metabolism positive feedback loop

Metastasis is a bottleneck in cancer treatment. Studies have shown the pivotal roles of long noncoding RNAs (lncRNAs) in regulating cancer metastasis; however, our understanding of lncRNAs in gastric cancer (GC) remains limited. RNA-seq was performed on metastasis-inclined GC tissues to uncover metastasis-associated lncRNAs, revealing upregulated small nucleolar RNA host gene 26 (SNHG26) expression, which predicted poor GC patient prognosis. Functional experiments revealed that SNHG26 promoted cellular epithelial–mesenchymal transition and proliferation in vitro and in vivo. Mechanistically, SNHG26 was found to interact with nucleolin (NCL), thereby modulating c-Myc expression by increasing its translation, and in turn promoting energy metabolism via hexokinase 2 (HK2), which facilitates GC malignancy. The increase in energy metabolism supplies sufficient energy to promote c-Myc translation and expression, forming a positive feedback loop. In addition, metabolic and translation inhibitors can block this loop, thus inhibiting cell proliferation and mobility, indicating potential therapeutic prospects in GC.

Nephroblastoma-specific dysregulated gene SNHG15 with prognostic significance: scRNA-Seq with bulk RNA-Seq data and experimental validation

Wilms tumor (WT) is the most common malignancy of the genitourinary system in children. Currently, the Integration of single-cell RNA sequencing (scRNA-Seq) and Bulk RNA sequencing (RNA-Seq) analysis of heterogeneity between different cell types in pediatric WT tissues could more accurately find prognostic markers, but this is lacking. RNA-Seq and clinical data related to WT were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Small nucleolar RNA host gene 15 (SNHG15) was identified as a risk signature from the TARGET dataset by using weighted gene co-expression network analysis, differentially expressed analysis and univariate Cox analysis. After that, the functional mechanisms, immunological and molecular characterization of SNHG15 were investigated at the scRNA-seq, pan-cancer, and RNA-seq levels using Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), ESTIMATE, and CIBERSORT. Based on scRNA-seq data, we identified 20 clusters in WT and annotated 10 cell types. Integration of single-cell and spatial data mapped ligand-receptor networks to specific cell types, revealing M2 macrophages as hubs for intercellular communication. In addition, in vitro cellular experiments showed that siRNAs interfering with SNHG15 significantly inhibited the proliferation and migration of G401 cells and promoted the apoptosis of G401 cells compared with the control group. The effect of siRNAs interfering with SNHG15 on EMT-related protein expression was verified by Western blotting assay. Thus, our findings will improve our current understanding of the pathogenesis of WT, and they are potentially valuable in providing novel prognosis markers for the treatment of WT.

Abstract 1552: Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulation

Abstract hosphatase and tensin homolog deleted on chromosome ten (PTEN) serves as a powerful tumor suppressor, and has been found to be downregulated in human bladder cancer (BC) tissues. Despite this observation, the mechanisms contributing to PTEN’s downregulation have remained elusive. In this study, we discovered that mice exposed to N-butyl-N-(4-hydroxybu-tyl)nitrosamine (BBN), a specific bladder chemical carcinogen, exhibited primary basal muscle invasive BC (BMIBC) accompanied by a pronounced reduction in PTEN protein expression in vivo. Utilizing a lncRNA deep sequencing high-throughput platform, along with gain- and loss-of-function analyses, we identified small nucleolar RNA host gene 1 (SNHG1) as a critical lncRNA that might drive the formation of primary BMIBCs in BBN-treated mice. Cell culture results further demonstrated that BBN exposure significantly induced SNHG1 in normal human bladder urothelial cell UROtsa. Notably, the ectopic expression of SNHG1 alone was sufficient to induce malignant transformation in human urothelial cells, while SNHG1 knockdown effectively inhibited anchorage-independent growth of human BMIBCs. Our detailed investigation revealed that SNHG1 overexpression led to PTEN protein degradation through its direct interaction with HUR. This interaction reduced HUR binding to ubiquitin-specific peptidase 8 (USP8) mRNA, causing degradation of USP8 mRNA and a subsequent decrease in USP8 protein expression. The downregulation of USP8, in turn, increased PTEN poly-ubiquitination and degradation, culminating in cell malignant transformation and BMIBC anchorage-independent growth. In vivo studies confirmed the downregulation of PTEN and USP8, as well as their positive correlations in both BBN-treated mouse bladder urothelium and tumor tissues of bladder cancer in nude mice.Our findings, for the first time, demonstrate that overexpressed SNHG1 competes with USP8 for binding to HUR. This competition attenuates USP8 mRNA stability and protein expression, leading to PTEN protein degradation, consequently, this process drives urothelial cell malignant transformation and fosters BMIBC growth and primary BMIBC formation. Citation Format: Chuanshu Huang, Tengda Li, Honglei Jin. Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1552.

Small nucleolar RNA host gene 18 controls vascular smooth muscle cell contractile phenotype and neointimal hyperplasia.

Long non-coding RNA (LncRNA) small nucleolar RNA host gene 18 (SNHG18) has been widely implicated in cancers. However, little is known about its functional involvement in vascular diseases. Herein, we attempted to explore a role for SNHG18 in modulating vascular smooth muscle cell (VSMC) contractile phenotype and injury-induced neointima formation. Analysis of single-cell RNA sequencing and transcriptomic datasets showed decreased levels of SNHG18 in injured and atherosclerotic murine and human arteries, which is positively associated with VSMC contractile genes. SNHG18 was upregulated in VSMCs by TGFβ1 through transcription factors Sp1 and SMAD3. SNHG18 gene gain/loss-of-function studies revealed that VSMC contractile phenotype was positively regulated by SNHG18. Mechanistic studies showed that SNHG18 promotes a contractile VSMC phenotype by up-regulating miR-22-3p. SNHG18 up-regulates miR-22 biogenesis and miR-22-3p production by competitive binding with the A-to-I RNA editing enzyme, adenosine deaminase acting on RNA-2 (ADAR2). Surprisingly, we observed that ADAR2 inhibited miR-22 biogenesis not through increasing A-to-I editing within primary miR-22, but by interfering with the binding of microprocessor complex subunit DGCR8 to primary miR-22. Importantly, perivascular SNHG18 overexpression in the injured vessels dramatically up-regulated the expression levels of miR-22-3p and VSMC contractile genes, and prevented injury-induced neointimal hyperplasia. Such modulatory effects were reverted by miR-22-3p inhibition in the injured arteries. Finally, we observed a similar regulator role for SNHG18 in human VSMCs and a decreased expression level of both SNHG18 and miR-22-3p in diseased human arteries; and we found that the expression level of SNHG18 was positively associated with that of miR-22-3p in both healthy and diseased human arteries. We demonstrate that SNHG18 is a novel regulator in governing VSMC contractile phenotype and preventing injury-induced neointimal hyperplasia. Our findings have important implications for therapeutic targeting snhg18/miR-22-3p signalling in vascular diseases.

LncRNA-SNHG5 mediates activation of hepatic stellate cells by regulating NF2 and Hippo pathway

Long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) is an oncogene found in various human cancers. However, it is unclear what role SNHG5 plays in activating hepatic stellate cells (HSCs) and liver fibrosis. In this study, SNHG5 was found to be upregulated in activated HSCs in vitro and in primary HSCs isolated from fibrotic liver in vivo, and inhibition of SNHG5 suppressed HSC activation. Notably, Neurofibromin 2 (NF2), the main activator for Hippo signalling, was involved in the effects of SNHG5 on HSC activation. The interaction between SNHG5 and NF2 protein was further confirmed, and preventing the combination of the two could effectively block the effects of SNHG5 inhibition on EMT process and Hippo signaling. Additionally, higher SNHG5 was found in chronic hepatitis B patients and associated with the fibrosis stage. Altogether, we demonstrate that SNHG5 could serve as an activated HSCs regulator via regulating NF2 and Hippo pathway.

Subverting the Canon: Novel Cancer-Promoting Functions and Mechanisms for snoRNAs.

Small nucleolar RNAs (snoRNAs) constitute a class of intron-derived non-coding RNAs ranging from 60 to 300 nucleotides. Canonically localized in the nucleolus, snoRNAs play a pivotal role in RNA modifications and pre-ribosomal RNA processing. Based on the types of modifications they involve, such as methylation and pseudouridylation, they are classified into two main families-box C/D and H/ACA snoRNAs. Recent investigations have revealed the unconventional synthesis and biogenesis strategies of snoRNAs, indicating their more profound roles in pathogenesis than previously envisioned. This review consolidates recent discoveries surrounding snoRNAs and provides insights into their mechanistic roles in cancer. It explores the intricate interactions of snoRNAs within signaling pathways and speculates on potential therapeutic solutions emerging from snoRNA research. In addition, it presents recent findings on the long non-coding small nucleolar RNA host gene (lncSNHG), a subset of long non-coding RNAs (lncRNAs), which are the transcripts of parental SNHGs that generate snoRNA. The nucleolus, the functional epicenter of snoRNAs, is also discussed. Through a deconstruction of the pathways driving snoRNA-induced oncogenesis, this review aims to serve as a roadmap to guide future research in the nuanced field of snoRNA-cancer interactions and inspire potential snoRNA-related cancer therapies.

LncRNA SNHG25 Predicts Poor Prognosis and Promotes Progression in Osteosarcoma via the miR-497-5p/SOX4 Axis.

Osteosarcoma is a disease that primarily affects adolescents with skeletal immaturity. LncRNAs are abnormally expressed and correlated with osteosarcoma patients' prognosis. We identified aberrant expression of LncRNA SNHG25 (small nucleolar RNA host gene 25) in osteosarcoma and analyzed the molecular mechanisms by which it regulates osteosarcoma progression. The expression levels of SNHG25 in tumour specimens and cells were measured by RTqPCR. Loss-of-function assays were conducted to investigate the functional role of SNHG25 in vitro and in vivo. Bioinformatic predictions, dual-luciferase reporter assays, and western blotting were performed to explore the possible underlying mechanisms. SNHG25 was highly expressed in osteosarcoma cells and tissues. The Kaplan-Meier curve showed that the survival rate of patients with high SNHG25 expression was significantly lower than those with low SNHG25 expression. Functional studies have indicated that inhibition of SNHG25 suppresses cell proliferation, migration, and invasion, while promoting apoptosis. SNHG25 knockdown suppresses osteosarcoma tumour growth in vivo. SNHG25 functions as a sponge for miR-497-5p in osteosarcoma cells. The level of SNHG25 was negatively correlated with that of miR-497-5p. The proliferation, invasion, and migration of osteosarcoma cells were restored by transfection of the miR-497-5p inhibitor in the SNHG25 knockdown group. SNHG25 was determined to function as an oncogene by promoting osteosarcoma cell proliferation, invasion, and migration through the miR-497-5p/SOX4 axis. Upregulation of SNHG25 expression indicated poor prognosis in patients with osteosarcoma, which showed that SNHG25 may serve as a potential therapeutic target and prognostic biomarker in osteosarcoma.

LncRNA SNHG1 promotes the progression of hepatocellular carcinoma by regulating the miR-7-5p/IGF2BP2 axis

Long noncoding RNA small nucleolar RNA host gene 1 (lncRNA SNHG1) plays a crucial role in the occurrence and progression of various tumors. This study investigates the function of lncRNA SNHG1 in hepatocellular carcinoma (HCC). We discovered that lncRNA SNHG1 is significantly upregulated in HCC and markedly enhances cell proliferation, migration, and invasion, while simultaneously suppressing apoptosis in HCC cells. Furthermore, lncRNA SNHG1 was found to downregulate miR-7-5p expression. Overexpression of lncRNA SNHG1 counteracted the suppression of HCC cell migration, proliferation, and invasion caused by miR-7-5p mimics, and reversed the miR-7-5p mimics' enhancement of apoptosis in HCC cells. Additionally, miR-7-5p was shown to negatively regulate IGF2BP2, with the silencing of IGF2BP2 diminishing the abilities of HCC cells to proliferate, migrate, and invade, and increasing their propensity for apoptosis. Overexpression of lncRNA SNHG1 negated these effects. Thus, lncRNA SNHG1 fosters HCC progression by upregulating IGF2BP2 expression through targeting miR-7-5p.

Integration of transcription regulation and functional genomic data reveals lncRNA SNHG6’s role in hematopoietic differentiation and leukemia

BackgroundLong non-coding RNAs (lncRNAs) are pivotal players in cellular processes, and their unique cell-type specific expression patterns render them attractive biomarkers and therapeutic targets. Yet, the functional roles of most lncRNAs remain enigmatic. To address the need to identify new druggable lncRNAs, we developed a comprehensive approach integrating transcription factor binding data with other genetic features to generate a machine learning model, which we have called INFLAMeR (Identifying Novel Functional LncRNAs with Advanced Machine Learning Resources).MethodsINFLAMeR was trained on high-throughput CRISPR interference (CRISPRi) screens across seven cell lines, and the algorithm was based on 71 genetic features. To validate the predictions, we selected candidate lncRNAs in the human K562 leukemia cell line and determined the impact of their knockdown (KD) on cell proliferation and chemotherapeutic drug response. We further performed transcriptomic analysis for candidate genes. Based on these findings, we assessed the lncRNA small nucleolar RNA host gene 6 (SNHG6) for its role in myeloid differentiation. Finally, we established a mouse K562 leukemia xenograft model to determine whether SNHG6 KD attenuates tumor growth in vivo.ResultsThe INFLAMeR model successfully reconstituted CRISPRi screening data and predicted functional lncRNAs that were previously overlooked. Intensive cell-based and transcriptomic validation of nearly fifty genes in K562 revealed cell type-specific functionality for 85% of the predicted lncRNAs. In this respect, our cell-based and transcriptomic analyses predicted a role for SNHG6 in hematopoiesis and leukemia. Consistent with its predicted role in hematopoietic differentiation, SNHG6 transcription is regulated by hematopoiesis-associated transcription factors. SNHG6 KD reduced the proliferation of leukemia cells and sensitized them to differentiation. Treatment of K562 leukemic cells with hemin and PMA, respectively, demonstrated that SNHG6 inhibits red blood cell differentiation but strongly promotes megakaryocyte differentiation. Using a xenograft mouse model, we demonstrate that SNHG6 KD attenuated tumor growth in vivo.ConclusionsOur approach not only improved the identification and characterization of functional lncRNAs through genomic approaches in a cell type-specific manner, but also identified new lncRNAs with roles in hematopoiesis and leukemia. Such approaches can be readily applied to identify novel targets for precision medicine.

The lncRNA Snhg11, a new candidate contributing to neurogenesis, plasticity, and memory deficits in Down syndrome.

Down syndrome (DS) stands as the prevalent genetic cause of intellectual disability, yet comprehensive understanding of its cellular and molecular underpinnings remains limited. In this study, we explore the cellular landscape of the hippocampus in a DS mouse model, the Ts65Dn, through single-nuclei transcriptional profiling. Our findings demonstrate that trisomy manifests as a highly specific modification of the transcriptome within distinct cell types. Remarkably, we observed a significant shift in the transcriptomic profile of granule cells in the dentate gyrus (DG) associated with trisomy. We identified the downregulation of a specific small nucleolar RNA host gene, Snhg11, as the primary driver behind this observed shift in the trisomic DG. Notably, reduced levels of Snhg11 in this region were also observed in a distinct DS mouse model, the Dp(16)1Yey, as well as in human postmortem brain tissue, indicating its relevance in Down syndrome. To elucidate the function of this long non-coding RNA (lncRNA), we knocked down Snhg11 in the DG of wild-type mice. Intriguingly, this intervention alone was sufficient to impair synaptic plasticity and adult neurogenesis, resembling the cognitive phenotypes associated with trisomy in the hippocampus. Our study uncovers the functional role of Snhg11 in the DG and underscores the significance of this lncRNA in intellectual disability. Furthermore, our findings highlight the importance of DG in the memory deficits observed in Down syndrome.

SNHG14 Elevates NFAT5 Expression Through Sequestering miR-375-3p to Promote MPP + -Induced Neuronal Apoptosis, Inflammation, and Oxidative Stress in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons. LncRNA small nucleolar RNA host gene 14 (SNHG14) was found to promote neuron injury in PD. Here, we investigated the mechanisms of SNHG14 in PD process. In vivo or in vitro PD model was established by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice or 1-methyl-4-phenylpyridinium (MPP +)-stimulated SK-N-SH cells. The expression of genes and proteins was measured by qRT-PCR and Western blot. In vitro assays were conducted using ELISA, CCK-8, colony formation, EdU, flow cytometry, and Western blot assays, respectively. The oxidative stress was evaluated by determining the production of superoxide dismutase (SOD) and malondialdehyde (MDA). The direct interactions between miR-375-3p and NFAT5 (Nuclear factor of activated T-cells 5) or SNHG14 was verified using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. SNHG14 and NFAT5 were elevated, while miR-375-3p was decreased in MPTP-mediated PD mouse model and MPP + -induced SK-N-SH cells. Knockdown of SNHG14 or NFAT5, or overexpression of miR-375-3p reversed MPP + -induced neuronal apoptosis, inflammation, and oxidative stress. Mechanistically, SNHG14 directly bound to miR-375, which targeted NFAT5. Inhibition of miR-375-3p abolished the inhibitory activity of SNHG14 knockdown on MPP + -evoked neuronal damage. Besides that, NFAT5 up-regulation counteracted the effects of miR-375-3p on MPP + -mediated neuronal damage. SNHG14 contributed to MPP + -induced neuronal injury by miR-375/NFAT5 axis, suggesting a new insight into the pathogenesis of PD.

Statement of Retraction: Knockdown of small nucleolar RNA host gene 10 (SNHG10) alleviates the injury of human neuroblastoma cells via the miR-1277-5p/insulin substrate receptor 2 axis

Statement of Retraction: Knockdown of small nucleolar RNA host gene 10 (SNHG10) alleviates the injury of human neuroblastoma cells via the miR-1277-5p/insulin substrate receptor 2 axis

Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulation

BackgroundPhosphatase and tensin homolog deleted on chromosome ten (PTEN) serves as a powerful tumor suppressor, and has been found to be downregulated in human bladder cancer (BC) tissues. Despite this observation, the mechanisms contributing to PTEN’s downregulation have remained elusive.MethodsWe established targeted genes’ knockdown or overexpressed cell lines to explore the mechanism how it drove the malignant transformation of urothelial cells or promoted anchorageindependent growth of human basal muscle invasive BC (BMIBC) cells. The mice model was used to validate the conclusion in vivo. The important findings were also extended to human studies.ResultsIn this study, we discovered that mice exposed to N-butyl-N-(4-hydroxybu-tyl)nitrosamine (BBN), a specific bladder chemical carcinogen, exhibited primary BMIBC accompanied by a pronounced reduction in PTEN protein expression in vivo. Utilizing a lncRNA deep sequencing high-throughput platform, along with gain- and loss-of-function analyses, we identified small nucleolar RNA host gene 1 (SNHG1) as a critical lncRNA that might drive the formation of primary BMIBCs in BBN-treated mice. Cell culture results further demonstrated that BBN exposure significantly induced SNHG1 in normal human bladder urothelial cell UROtsa. Notably, the ectopic expression of SNHG1 alone was sufficient to induce malignant transformation in human urothelial cells, while SNHG1 knockdown effectively inhibited anchorage-independent growth of human BMIBCs. Our detailed investigation revealed that SNHG1 overexpression led to PTEN protein degradation through its direct interaction with HUR. This interaction reduced HUR binding to ubiquitin-specific peptidase 8 (USP8) mRNA, causing degradation of USP8 mRNA and a subsequent decrease in USP8 protein expression. The downregulation of USP8, in turn, increased PTEN polyubiquitination and degradation, culminating in cell malignant transformation and BMIBC anchorageindependent growth. In vivo studies confirmed the downregulation of PTEN and USP8, as well as their positive correlations in both BBN-treated mouse bladder urothelium and tumor tissues of bladder cancer in nude mice.ConclusionsOur findings, for the first time, demonstrate that overexpressed SNHG1 competes with USP8 for binding to HUR. This competition attenuates USP8 mRNA stability and protein expression, leading to PTEN protein degradation, consequently, this process drives urothelial cell malignant transformation and fosters BMIBC growth and primary BMIBC formation.