scholarly journals Cerebellar Long Noncoding RNA Expression Profile in a Niemann-Pick C Disease Mouse Model

2021 ◽  
Author(s):  
Shiqian Han ◽  
Meng Ren ◽  
Tianyin Kuang ◽  
Mao Pang ◽  
Dongwei Guan ◽  
...  
Keyword(s):  
Expression Profile ◽  
Noncoding Rna ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Rna Seq ◽  
Lysosomal Storage ◽  
Lncrna Expression ◽  
Type C ◽  
Niemann Pick

AbstractNiemann-Pick type C (NP-C) disease is a neurodegenerative lysosomal storage disorder primarily caused by mutations in NPC1. However, its pathogenesis remains poorly understood. While mounting evidence has demonstrated the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of neurodegenerative disorders, the lncRNA expression profile in NP-C has not been determined. Here, we used RNA-seq analysis to determine lncRNA and mRNA expression profiles of the cerebella of NPC1−/− mice. We found that 272 lncRNAs and 856 mRNAs were significantly dysregulated in NPC1−/− mice relative to controls (≥ 2.0-fold, p < 0.05). Quantitative real-time PCR (qRT‐PCR) was utilized to validate the expression of selected lncRNAs and mRNAs. Next, a lncRNA-mRNA coexpression network was employed to examine the potential roles of the differentially expressed (DE) lncRNAs. Functional analysis revealed that mRNAs coexpressed with lncRNAs are mainly linked to immune system–related processes and neuroinflammation. Moreover, knockdown of the lncRNA H19 ameliorated changes in ROS levels and cell viability and suppressed the lipopolysaccharide (LPS)–induced inflammatory response in vitro. Our findings indicate that dysregulated lncRNA expression patterns are associated with NP-C pathogenesis and offer insight into the development of novel therapeutics based on lncRNAs.

scholarly journals Human iNSC-derived brain organoid model of lysosomal storage disorder in Niemann–Pick disease type C

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Seung-Eun Lee ◽  
Nari Shin ◽  
Myung Geun Kook ◽  
Dasom Kong ◽  
Nam Gyo Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Lysosomal Storage Disorder ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Storage Disorder ◽  
Niemann Pick ◽  
Pick Disease

AbstractRecent studies on developing three-dimensional (3D) brain organoids from stem cells have allowed the generation of in vitro models of neural disease and have enabled the screening of drugs because these organoids mimic the complexity of neural tissue. Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in the NPC1 or NPC2. The pathological features underlying NPC are characterized by the abnormal accumulation of cholesterol in acidic compartments, including late endosomes and lysosomes. Due to the inaccessibility of brain tissues from human NPC patients, we developed NPC brain organoids with induced neural stem cells from NPC patient-derived fibroblasts. NPC organoids exhibit significantly reduced size and proliferative ability, which are accompanied by accumulation of cholesterol, impairment in neuronal differentiation, and autophagic flux and dysfunction of lysosomes; therefore, NPC organoids can recapitulate the main phenotypes of NPC patients. Furthermore, these pathological phenotypes observed in NPC organoids were reversed by treatment with valproic acid and HPBCD, which are known to be an effective treatment for several neurodegenerative diseases. Our data present patient-specific phenotypes in 3D organoid-based models of NPC and highlight the application of this model to drug screening in vitro.

scholarly journals Circular RNA Expression Profiles and Features in NAFLD Mice: A Study Using RNA-Seq Data

2020 ◽  
Author(s):  
Xinlu Yuan ◽  
Jianjun Diao ◽  
Anqing Du ◽  
Song Wen ◽  
Ligang Zhou ◽  
...  
Keyword(s):  
Expression Profile ◽  
Noncoding Rna ◽  
Expression Profiles ◽  
Circular Rna ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Mice Model ◽  
Specific Expression ◽  
Nonalcoholic Fatty Liver ◽  
Sequencing Method

Abstract Background: Nonalcoholic fatty liver disease (NAFLD) is primarily characterized by the hepatic cholesterol accumulation. Circular RNA (circRNA), one of noncoding RNA, involves in many liver diseases progression. However, no recent studies on circRNA expression profiles in NAFLD have been reported previously.Methods: A NAFLD mouse model was constructed by providing high-fat diet (HFD) for 32 weeks. The circRNAs expression profile in normal mice and NAFLD mice were determined using high-output RNA sequencing method and bioinformatics methods, while the differentially expressed circRNAs were confirmed using Sanger sequencing and qRT-PCR. The circRNA-miRNA network was also predicted. The biological functions of circRNAs were annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG).Results: The results demonstrated the successful construction of NAFLD mice model by immunohistology and serology assay. In total, 93 dysregulated circRNAs were observed, including 57 upregulated circRNAs and 36 downregulated circRNAs, in the NAFLD group. The circRNA-miRNA network revealed the complex interaction between circRNAs and its potential miRNA targets in NAFLD. The characteristic of tissue-specific expression in circRNA was demonstrated. The differentially expressed circRNAs with important biological function were also annotated using GO and KEGG. Both DDAH1 and VAV3 genes were found to be associated with the NAFLD development.Conclusions: Taken together, this study demonstrated the circRNAs expression profile and features in NAFLD, which may provide potential biological markers for the pathogenesis of NAFLD.

scholarly journals Long noncoding RNA SGO1-AS1 inactivates TGFβ signaling by facilitating TGFB1/2 mRNA decay and inhibits gastric carcinoma metastasis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Donglan Huang ◽  
Ke Zhang ◽  
Wenying Zheng ◽  
Ruixin Zhang ◽  
Jiale Chen ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Noncoding Rna ◽  
Mrna Decay ◽  
Expression Profiles ◽  
Regulatory Mechanisms ◽  
Mesenchymal Transition ◽  
Lncrna Expression ◽  
Carcinoma Metastasis

Abstract Background Although thousands of long noncoding RNAs (lncRNAs) have been annotated, only a few lncRNAs have been characterized functionally. In this study, we aimed to identify novel lncRNAs involved in the progression of gastric carcinoma (GC) and explore their regulatory mechanisms and clinical significance in GC. Methods A lncRNA expression microarray was used to identify differential lncRNA expression profiles between paired GCs and adjacent normal mucosal tissues. Using the above method, the lncRNA SGO1-AS1 was selected for further study. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) were performed to detect SGO1-AS1 expression in GC tissues. Gain-of-function and loss-of-function analyses were performed to investigate the functions of SGO1-AS1 and its upstream and downstream regulatory mechanisms in vitro and in vivo. Results SGO1-AS1 was downregulated in gastric carcinoma tissues compared to adjacent normal tissues, and its downregulation was positively correlated with advanced clinical stage, metastasis status and poor patient prognosis. The functional experiments revealed that SGO1-AS1 inhibited GC cell invasion and metastasis in vitro and in vivo. Mechanistically, SGO1-AS1 facilitated TGFB1/2 mRNA decay by competitively binding the PTBP1 protein, resulting in reduced TGFβ production and, thus, preventing the epithelial-to-mesenchymal transition (EMT) and metastasis. In addition, in turn, TGFβ inhibited SGO1-AS1 transcription by inducing ZEB1. Thus, SGO1-AS1 and TGFβ form a double-negative feedback loop via ZEB1 to regulate the EMT and metastasis. Conclusions SGO1-AS1 functions as an endogenous inhibitor of the TGFβ pathway and suppresses gastric carcinoma metastasis, indicating a novel potential target for GC treatment.

scholarly journals Gene Expression Profile of the Human Colorectal Carcinoma LoVo Cells Treated With Sporamin and Thapsigargin

2021 ◽  
Vol 11 ◽  
Author(s):  
Chun Yang ◽  
Si-Jia Chen ◽  
Bo-Wen Chen ◽  
Kai-Wen Zhang ◽  
Jing-Jie Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Ipomoea Batatas ◽  
Expression Profiles ◽  
Rna Seq ◽  
Ppi Network ◽  
Illumina Platform

Sporamin, a proteinase inhibitor isolated from the sweet potato (Ipomoea batatas), has shown promising anticancer effect against colorectal cancer (CRC) in vitro and in vivo but its mechanisms of action are poorly understood. In the present study, high throughput RNA sequencing (RNA-seq) technology was applied to explore the transcriptomic changes induced by sporamin in the presence of thapsigargin (TG), a non-12-O-tetradecanolphorbol-13-acetate type cancer promoter, in the LoVo human CRC cells. Cellular total RNA was extracted from the cells after they were treated with vehicle (CTL), 1 μM of thapsigargin (TG), or 1 μM of TG plus 30 μM of sporamin (TGSP) for 24 h. The migratory capacity of the cells was determined by wound healing assay. The gene expression profiles of the cells were determined by RNA-seq on an Illumina platform. GO enrichment analysis, KEGG pathway analysis, protein-protein interaction (PPI) network construction, and transcription factors (TF) prediction were all performed based on the differentially expressed genes (DEGs) across groups with a series of bioinformatics tools. Finally, the effect and potential molecular targets of the sporamin at the transcriptome level were evaluated. Sporamin significantly inhibited the migration of cells induced by TG. Among the 17915 genes detected in RNA-seq, 46 DEGs were attributable to the effect of sporamin. RT-PCR experiment validated that the expression of RGPD2, SULT1A3, and BIVM-ERCC5 were up-regulated while NYP4R, FOXN1, PAK6, and CEACAM20 were down-regulated. Sporamin enhanced the mineral absorption pathway, worm longevity regulating pathway, and pyrimidine metabolism pathway. Two TFs (SMIM11A and ATOH8) were down-regulated by sporamin. HMOX1 (up-regulated) and NME1-NME2 (down-regulated) were the main nodes in a PPI network consisting of 16 DEGs that were modulated by sporamin in the presence of TG. Sporamin could favorably alter the gene expression profile of CRC cells, up-regulating the genes that contribute to the homeostasis of intracellular metal ions and the activities of essential enzymes and DNA damage repairment. More studies are warranted to verify its effect on specific genes and delineate the mechanism of action implicated in the process.

scholarly journals Release of acidic store calcium is required for effective priming of the NLRP3 inflammasome

2022 ◽  
Author(s):  
Nick Platt ◽  
Dawn Shepherd ◽  
Yuzhe Weng ◽  
Grant Charles Churchill ◽  
Antony Galione ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Calcium Release ◽  
Inflammatory Responses ◽  
Lysosomal Storage ◽  
Release Channel ◽  
Type C ◽  
Niemann Pick ◽  
Lysosomal Protein

The lysosome is a dynamic signaling organelle that is critical for cell functioning. It is a regulated calcium store that can contribute to Ca2+-regulated processes via both local calcium release and more globally by influencing ER Ca2+release. Here, we provide evidence from studies of an authentic mouse model of the lysosomal storage disease Niemann-Pick Type C (NPC) that has reduced lysosomal Ca2+ levels, and genetically modified mice in which the two-pore lysosomal Ca2+ release channel family are deleted that lysosomal Ca2+ signaling is required for normal pro-inflammatory responses. We demonstrate that production of the pro-inflammatory cytokine IL-1beta via the NLRP3 inflammasome is significantly reduced in murine Niemann-Pick Type C, the inhibition is selective because secretion of TNF alpha is not diminished, and it is a consequence of inefficient inflammasome priming. Synthesis of precursor ProIL-1 beta is significantly reduced in macrophages genetically deficient in the lysosomal protein Npc1, which is mutated in most clinical cases of NPC, and in wild type cells in which Npc1 activity is pharmacologically inhibited. Comparable reductions in ProIL-1 beta generation were measured in vitro and in vivo by macrophages genetically altered to lack expression of the two-pore lysosomal Ca2+ release channels Tpcn1 or Tpcn2. These data demonstrate a requirement for lysosome-dependent Ca2+ signaling in the generation of specific pro-inflammatory responses.

scholarly journals Long noncoding RNA expression profile of mouse cementoblasts under compressive force

2019 ◽  
Vol 89 (3) ◽  
pp. 455-463 ◽  
Author(s):  
Hao Liu ◽  
Yiping Huang ◽  
Yingying Zhang ◽  
Yineng Han ◽  
Yixin Zhang ◽  
...  
Keyword(s):  
Expression Profile ◽  
Long Noncoding Rna ◽  
Functional Annotation ◽  
Noncoding Rna ◽  
Compressive Loading ◽  
Compressive Force ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Lncrna Expression ◽  
Qrt Pcr

ABSTRACT Objectives: To investigate the long noncoding RNA (lncRNA) expression profile of cementoblasts under compressive force. Materials and Methods: Mouse cementoblasts were exposed to compression (1.5 g/cm2) for 8 hours. RNA sequencing (RNA-seq) was performed to compare the transcriptomes of the compressed and control cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate five of the differentially expressed lncRNAs of interest. Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were also performed. Results: A total of 70 lncRNAs and 521 mRNAs were differentially regulated in cementoblasts subjected to compressive loading. Among the differentially expressed lncRNAs, 57 were upregulated and 13 downregulated. The expression levels of the five selected lncRNAs (Prkcz2, Hklos, Trp53cor1, Gdap10, and Ak312-ps) were validated by qRT-PCR and consistent with the RNA-seq results. GO functional annotation demonstrated upregulation of genes associated with cellular response to hypoxia and apoptotic processes during compressive loading. KEGG analysis identified the crucial pathways involving the hypoxia-inducing factor-1α, forkhead box O, and mammalian target of rapamycin signaling pathways. Conclusions: Mechanical compression changes the lncRNA expression profile of cementoblasts, providing important references for further investigation into the role and regulation of lncRNAs in compressed cementoblasts and root resorption during orthodontic treatment.

scholarly journals Long Noncoding RNA DICER1-AS1 Functions in Methylation Regulation on the Multi-Drugresistance of Osteosarcoma Cells via miR-34a-5p and GADD45A

2021 ◽  
Vol 11 ◽  
Author(s):  
Feng Wang ◽  
Lingsuo Kong ◽  
Youguang Pu ◽  
Fengmei Chao ◽  
Chunbao Zang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Therapeutic Target ◽  
Promoter Region ◽  
Noncoding Rna ◽  
Expression Profiles ◽  
Methylation Status ◽  
Rna Seq ◽  
Loss Of Function ◽  
Potential Biomarker

Osteosarcoma (OS) is a common malignant bone tumor that commonly occurs in children and adolescents. Long noncoding RNAs (lncRNAs) are recognized as a novel class of regulators of gene expression associated with tumorigenesis. However, the effect and mechanism of lncRNAs in OS tumorigenesis and drug resistance have not been characterized. The purpose of the study is to screen potential biomarker and therapeutic target against OS. We compared the lncRNA expression profiles between OS cell lines with different drug resistance levels using RNA-seq analysis and found that lncRNA DICER1-AS1 was significantly differentially expressed in multi-drugresistant OS cells SJSA-1 versus multi-drugsensitive OS cells G-292. Bisulfite Sequencing PCR (BSP) assay was performed to analyze the differential methylation status of the promoter region of DICER1-AS1 in four OS cells. Subsequently, in vitro gain- and loss-of-function experiments demonstrated the roles of DICER1-AS1 and miR-34a-5p in the multi-drugresistance of OS cells. The main findings is that DICER1-AS1 directly binds to miR-34a-5p, and their expression has a negative correlation with each other. The hypermethylation of the promoter region of DICER1-AS1 silenced its expression in the drugresistant cells SJSA-1 and MNNG/HOS. Moreover, we found that growth arrest and DNA damage-inducible alpha (GADD45A) participates in the DICER1-AS1/miR-34a-5p-regulated drug resistance of OS cells, probably via the cell cycle/pRb-E2F pathway. Our results revealed DICER1-AS1/miR-34a-5p-regulated drug resistance of OS cells, a new lncRNA-regulated network in OS tumorigenesis, suggested that DICER1-AS1 can be considered as a potential biomarker and therapeutic target against OS cells.

scholarly journals Circular RNA expression profiles and features in NAFLD mice: a study using RNA-seq data

2020 ◽  
Author(s):  
Xinlu Yuan ◽  
Jianjun Diao ◽  
Anqing Du ◽  
Song Wen ◽  
Ligang Zhou ◽  
...  
Keyword(s):  
Expression Profile ◽  
Noncoding Rna ◽  
Expression Profiles ◽  
Circular Rna ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Mice Model ◽  
Specific Expression ◽  
Nonalcoholic Fatty Liver ◽  
Sequencing Method

Abstract Background: Nonalcoholic fatty liver disease (NAFLD) is primarily characterized by the hepatic cholesterol accumulation. Circular RNA (circRNA), one of noncoding RNA, involves in many liver diseases progression. However, no recent studies on circRNA expression profiles in NAFLD have been reported previously. Methods: A NAFLD mouse model was constructed by providing high-fat diet (HFD) for 32 weeks. The circRNAs expression profile in normal mice and NAFLD mice were determined using high-output RNA sequencing method and bioinformatics methods, while the differentially expressed circRNAs were confirmed using Sanger sequencing and qRT-PCR. The circRNA-miRNA network was also predicted. The biological functions of circRNAs were annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Results: The results demonstrated the successful construction of NAFLD mice model by immunohistology and serology assay. In total, 93 dysregulated circRNAs were observed, including 57 upregulated circRNAs and 36 downregulated circRNAs, in the NAFLD group. The circRNA-miRNA network revealed the complex interaction between circRNAs and its potential miRNA targets in NAFLD. The characteristic of tissue-specific expression in circRNA was demonstrated. The differentially expressed circRNAs with important biological function were also annotated using GO and KEGG. Both DDAH1 and VAV3 genes were found to be associated with the NAFLD development. Conclusions: Taken together, this study demonstrated the circRNAs expression profile and features in NAFLD, which may provide potential biological markers for the pathogenesis of NAFLD.

scholarly journals Circular RNA expression profiles and features in NAFLD mice: a study using RNA-seq data

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Xinlu Yuan ◽  
Jianjun Diao ◽  
Anqing Du ◽  
Song Wen ◽  
Ligang Zhou ◽  
...  
Keyword(s):  
Expression Profile ◽  
Noncoding Rna ◽  
Expression Profiles ◽  
Circular Rna ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Mice Model ◽  
Specific Expression ◽  
Nonalcoholic Fatty Liver ◽  
Sequencing Method

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is primarily characterized by the hepatic cholesterol accumulation. Circular RNA (circRNA), one of noncoding RNA, involves in many liver diseases progression. However, no recent studies on circRNA expression profiles in NAFLD have been reported previously. Methods A NAFLD mouse model was constructed by providing high-fat diet (HFD) for 32 weeks. The circRNAs expression profile in normal mice and NAFLD mice were determined using high-output RNA sequencing method and bioinformatics methods, while the differentially expressed circRNAs were confirmed using Sanger sequencing and qRT-PCR. The circRNA-miRNA network was also predicted. The biological functions of circRNAs were annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Results The results demonstrated the successful construction of NAFLD mice model by immunohistology and serology assay. In total, 93 dysregulated circRNAs were observed, including 57 upregulated circRNAs and 36 downregulated circRNAs, in the NAFLD group. The circRNA-miRNA network revealed the complex interaction between circRNAs and its potential miRNA targets in NAFLD. The characteristic of tissue-specific expression in circRNA was demonstrated. The differentially expressed circRNAs with important biological function were also annotated using GO and KEGG. Both DDAH1 and VAV3 genes were found to be associated with the NAFLD development. Conclusions Taken together, this study demonstrated the circRNAs expression profile and features in NAFLD, which may provide potential biological markers for the pathogenesis of NAFLD.

scholarly journals Long Noncoding RNA SGO1-AS1 Inactivates TGFβ Signaling by Facilitating TGFB mRNA Decay and Inhibits Gastric Carcinoma Metastasis

2021 ◽  
Author(s):  
Donglan Huang ◽  
Ke Zhang ◽  
Wenying Zheng ◽  
Ruixin Zhang ◽  
Jiale Chen ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Noncoding Rna ◽  
Mrna Decay ◽  
Expression Profiles ◽  
Regulatory Mechanisms ◽  
Mesenchymal Transition ◽  
Lncrna Expression ◽  
Carcinoma Metastasis

Abstract Background: Although thousands of long noncoding RNAs (lncRNAs) have been annotated, only a limited number of them have been characterized functionally. In this study, we aimed to identify novel lncRNAs involved in the progression of gastric carcinoma (GC) and explore their regulatory mechanisms and clinical significance in GC.Methods: LncRNA expression microarray was used to identify differential lncRNA expression profiles between paired GCs and adjacent normal mucosa tissues. Using the above method, lncRNA SGO1-AS1 was picked out for further study. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) were performed to detect SGO1-AS1 expression in GC tissues. Gain-of-function and loss-of-function analyses were performed to investigate the functions of SGO1-AS1 and its upstream and downstream regulatory mechanisms in vitro and in vivo. Results: SGO1-AS1 was downregulated in gastric carcinoma tissues compared to adjacent normal tissues, and its downregulation was positively correlated with advanced clinical stage, metastasis status and poor patient prognosis. Functional experiments revealed that SGO1-AS1 inhibited GC cell invasion and metastasis in vitro and in vivo. Mechanistically, SGO1-AS1 facilitated TGFB1/2 mRNA decay by competitively binding the PTBP1 protein, which resulted in reduced TGFβ production and thus prevented the epithelial-to-mesenchymal transition (EMT) and metastasis. In addition, TGFβ in turn could inhibited SGO1-AS1 transcription by inducing ZEB1. Thus, SGO1-AS1 and TGFβ form a double-negative feedback loop via ZEB1 to regulate EMT and metastasis.Conclusions: SGO1-AS1 functions as an endogenous inhibitor of the TGFβ pathway and suppresses gastric carcinoma metastasis, indicating a novel potential target for GC treatment.

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