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Imprinted lncrna KCNQ1OT1 regulates CDKN1C expression through promoter binding and chromatin folding in pigs

GENE 2024年 923卷 148590页

作者： Zhou, Yongfeng Yu, Hao Zhang, Daoyu Wang, Zhengzhu Li, Qi An, Xinglan Zhang, Sheng Li, Ziyi Jilin Univ Hosp 1 Key Lab Organ Regenerat & Transplantat Minist Educ Changchun 130021 Peoples R China Jilin Univ Coll Anim Sci Changchun Peoples R China First Hosp Jilin Univ Genet Diag Ctr Changchun Peoples R China Shenzhen Univ South China Hosp Shenzhen Peoples R China

long noncoding rnas (lncrnas) are implicated in a number of regulatory functions in eukaryotic genomes. In humans, KCNQ1OT1 is a 91 kb imprinted lncrna that inhibits multiple surrounding genes in cis. Among them, CDKN1C is closely related to KCNQ1OT1 and is involved in multiple epigenetic disorders. Here, we found that pigs also had a relatively conserved paternal allele expressing KCNQ1OT1 and had a shorter 5 ' end (similar to 27 kb) compared to human KCNQ1OT1. Knockdown of KCNQ1OT1 using antisense oligonucleotides (ASO) showed that upregulation of CDKN1C expression in pigs. However, porcine KCNQ1OT1 did not affect the DNA methylation status of the CpG islands in the promoters of KCNQ1OT1 and CDKN1C. Inhibition of DNA methyltransferase using Decitabine treatment resulted in a significant increase in both KCNQ1OT1 and CDKN1C expression, suggesting that the regulation between KCNQ1OT1 and CDKN1C may not be dependent on rna interference. Further use of chromosome conformation capture and reverse transcription-associated trap detection in the region where CDKN1C was located revealed that KCNQ1OT1 bound to the CDKN1C promoter and affected chromosome folding. Phenotypically, inhibition of KCNQ1OT1 at the cumulus-oocyte complex promoted cumulus cell transformation, and to upregulated the expression of ALPL at the early stage of osteogenic differentiation of porcine bone marrow mesenchymal stem cells. Our results confirm that the expression of KCNQ1OT1 imprinting in pigs as well as porcine KCNQ1OT1 regulates the expression of CDKN1C through direct promoter binding and chromatin folding alteration. And this regulatory mechanism played an important role in cell differentiation.

关键词： Imprinted gene long-noncoding rna DNA methylation Chromosome folding Pigs

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Effects of myo-inositol on regulating glucose and lipid metabolism and alternative splicing events coexpressed with lncrnas in the liver tissues of diabetic mice

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HELIYON 2024年第11期10卷 e32460页

作者： Li, Jin'e Huang, Qiulan Nie, Qin Luo, Yunfei Zeng, Haixia Zhang, Yuying He, Xiaoju Liu, Jianping Nanchang Univ Affiliated Hosp 2 Jiangxi Med Coll Dept Endocrinol & Metab Nanchang 330006 Jiangxi Peoples R China Inst Study Endocrinol & Metab Jiangxi Prov Nanchang 330006 Jiangxi Peoples R China Nanchang Univ Affiliated Hosp 2 Jiangxi Med Coll Dept Obstet & Gynecol Nanchang 330006 Jiangxi Peoples R China Wuhan Univ Zhongnan Hosp Wuhan 430071 Hubei Peoples R China 1 Minde Rd Nanchang 330000 Jiangxi Peoples R China

Objective: Recent studies have shown that gene alternative splicing (AS) and long noncoding rnas (lncrnas) are involved in diabetes mellitus (DM) and its complications. Currently, myo-inositol (MI) is considered as effective for the treatment of insulin resistance and lipid metabolism disorders in diabetes patients. We hope to better explore the potential roles of gene AS and lncrnas in liver glucose and lipid metabolism in diabetes, as well as the effects of myo-inositol treatment, through transcriptome analysis. Methods: This study analysed glucose and lipid metabolism-related biochemical indicators and liver HE staining in four groups of mice: the control group (Ctrl group), the diabetes group (DM group), the myo-inositol treatment group (MI group), and the metformin treatment group (Met group). The changes in relevant gene-regulated alternative splicing events (RASEs) and lncrnas were analysed by rna sequencing of liver tissue, and coexpression analysis and functional enrichment analysis were used to predict the possible lncrnas and RASEs involved in liver glucose and lipid metabolism. Result: Metformin and myo-inositol alleviated insulin resistance, lipid metabolism disorders, and hepatic steatosis in diabetic mice. Transcriptome sequencing analysis revealed differential splicing events of genes related to lipid metabolism and differentially expressed lncrnas (DElncrnas). Six different lncrnas and their potentially interacting splicing events were predicted. Conclusion: The present study revealed novel changes in RASEs and lncrnas in the livers of diabetic mice following treatment with myo-inositol, which may shed light on the potential mechanisms by which myo-inositol delays and treats the progression of hepatic glucose and lipid metabolism in diabetes.

关键词： Diabetes mellitus Liver Glucose and lipid metabolism Myo-inositol Alternative splicing long-noncoding rna

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FIMICS: A panel of long noncoding rnas for cardiovascular conditions

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HELIYON 2023年第1期9卷 e13087页

作者： Firat, Huseyin Zhang, Lu Baksi, Shounak Leszek, Przemyslaw Schordan, Eric Ounzain, Samir Kottwitz, Jan Patriki, Dimitri Heidecker, Bettina Luscher, Thomas F. Pedrazzini, Thierry Devaux, Yvan Luxembourg Inst Hlth Cardiovasc Res Unit Strassen Luxembourg Inst Cardiol Heart Failure & Transplantol Dept Warsaw Poland Firalis SA Huningue France HAYA Therapeut Lausanne Vaud Switzerland Kantonsspital St Gallen Div Anesthesiol Intens Care Rescue & Pain Med CH-9007 St Gallen Switzerland Univ Hosp Zurich Dept Cardiol Raemistr 100 CH-8091 Zurich Switzerland Charite Univ Med Berlin Berlin Germany Imperial Coll London Royal Brompton & Harefield Hosp GSTT London England Kings Coll London London England Univ Zurich Ctr Mol Cardiol Zurich Switzerland Univ Lausanne Dept Cardiovasc Med Expt Cardiol Unit Med Sch Lausanne Switzerland

Cardiovascular disorders such as heart failure are leading causes of mortality. Patient stratifica-tion via identification of novel biomarkers could improve management of cardiovascular diseases of complex etiologies. long-noncoding rnas (lncrnas) are highly tissue-specific in nature and have emerged as important biomarkers in human diseases. In this study, we aimed to identify cardiac-enriched lncrnas as potential biomarkers for cardiovascular *** rna sequencing and quantitative PCR identified differentially expressed lncrnas be-tween failing and non-failing hearts. An independent dataset was used to evaluate the enrichment of lncrnas in normal hearts. We identified a panel of 2906 lncrnas, named FIMICS, that were either cardiac-enriched or differentially expressed between failing and non-failing hearts. Expression of lncrnas in blood samples differentiated patients with myocarditis and acute myocardial infarction. We hereby present the FIMICS panel, a readily available tool to provide insights into cardio-vascular pathologies and which could be helpful for diagnosis, monitoring and prognosis purposes.

关键词： Biomarker Heart failure Cardiovascular condition long-noncoding rna Deep rna sequencing Cardiac enriched rna

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Distinct gene expression patterns of SOX2 and SOX2OT variants in different types of brain tumours

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JOUrnaL OF GENETICS 2023年第1期102卷 25-25页

作者： Fouani, Youssef Gholipour, Akram Oveisee, Maziar Shahryari, Alireza Saberi, Hooshang Mowla, Seyed Javad Malakootian, Mahshid Tarbiat Modares Univ Fac Biol Sci Dept Mol Genet Tehran *** Iran Iran Univ Med Sci Cardiogenet Res Ctr Rajaie Cardiovasc Med & Res Ctr Tehran *** Iran Bam Univ Med Sci Sch Med Bam *** Iran Univ Tehran Med Sci Dept Neurosurg Tehran *** Iran Univ Tehran Med Sci Brain & Spinal Cord Injuries Repair Res Ctr Tehran *** Iran

Numerous investigations have been recently published on the dysregulated expression of long-noncoding rnas (lncrnas) in various cancer types, emphasizing that abnormal lncrna expression is a major contributor to tumourigenesis. A broad spectrum of lncrnas is expressed in the central nervous system, where these rnas seem to play key roles in brain development and function. In addition to expressing SOX2, a master regulator of pluripotency that lies within its third intron, lncrna SOX2OT has a proposed role in regulating neural development. Based on our previous studies, alternative splicing of SOX2OT generates two alternatively spliced variants (SOX2OT-S1 and SOX2OT-S2). The present study investigated the expression patterns of SOX2OT variants and SOX2 in three principal types of brain tumours (gliomas, meningiomas and pituitary adenomas) and in four brain tumour cell lines (U87-MG, 1321N1, A172 and DAOY). Total rna was extracted from 34 human brain tumour specimens, and the expression profile of target genes was measured using a real-time reverse transcription PCR approach. Our data revealed distinct expression patterns for SOX2OT variants and SOX2 in the brain tumour samples, indicating their potential involvement in brain tumourigenesis. Moreover, our results highlighted the potential usefulness of SOX2OT-S1, SOX2OT-S2, and SOX2 in molecular diagnosis and brain tumour classification.

关键词： long-noncoding rna SOX2OT-S1 SOX2OT-S2 SOX2 cancer stem cell brain tumour

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Deciphering the role of non-coding rnas SNHG18, HOXA11-AS, MEG3, and MDC1-AS1 in glioma patients: A combined experimental and computational study

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GENE REPORTS 2024年 36卷

作者： Mohammadian, Kamal Moradi, Arash Shabani, Mansoureh Kazemi, Somayeh Ganji, Shahla Mohammad Hamadan Univ Med Sci Dept Radiat Oncol Hamadan Iran Hamadan Univ Med Sci Canc Res Ctr Hamadan Iran Natl Inst Genet Engn & Biotechnol Med Biotechnol Inst Dept Mol Med Tehran Iran Islamic Azad Univ Sci & Res Branch Tehran Iran Islamic Azad Univ Tehran Med Sci Branch Tehran Iran

Background: Gliomas are brain tumours categorised into low-grade (I and II) and high-grade (III and IV). Unfortunately, patients with high-grade gliomas have a poor prognosis, which is why researchers are working to improve their management. One crucial area of study is the understanding of glioma tumorigenesis and progression. Recent research has shown that long non-coding rnas (lncrnas) play a potential role in this process. Material and methods: We evaluated the expression of SNHG18, HOXA11-AS, MEG3, and MDC1-AS1 in 150 paraffin tissue block samples, including 37 low-grade gliomas, 58 high-grade gliomas, and 55 non-tumoural tissues. After rna extraction and complementary DNA synthesis (cDNA), we used probe-based qPCR to evaluate the lncrna expression level, followed by statistical analyses. Results: The qRT-PCR analysis revealed differential expression patterns of lncrnas in tumour tissues compared to controls. In low-grade tumours, SNHG18 and HOXA11-AS were upregulated (SNHG18: 1.78 +/- 0.21, p < 0.001;HOXA11-AS: 1.24 +/- 0.60, p < 0.001), while MEG3 and MDC1-AS1 were downregulated (MEG3: 0.72 +/- 0.17, p < 0.001;MDC1-AS1: 0.24 +/- 0.18, p < 0.001). In high-grade tumours, SNHG18 and HOXA11-AS were further upregulated (SNHG18: 3.16 +/- 0.88, p < 0.001;HOXA11-AS: 3.83 +/- 0.82, p < 0.001), and MEG3 and MDC1-AS1 remained downregulated (MEG3: 0.49 +/- 0.29, p < 0.001;MDC1-AS1: 0.15 +/- 0.09, p < 0.001). The bioinformatic-based study conveyed that the alteration in lncrnas expression leads to dysregulation of rna Polymerase II, which is observed in glioblastoma. Conclusion: Our results suggest that SNHG18 and HOXA11-AS (up-regulated) may act as oncogenes in high-grade gliomas. In contrast, the downregulation of MEG3 and MDC1-AS1 in high-grade gliomas could be related to tumour suppressor properties. Therefore, it could be assumed that the expression levels of these lncrnas may serve as potential biomarkers for diagnostic and therapeutic purposes.

关键词： Biomarkers Gene expression Glioma long-noncoding rna qPCR

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Effect of simulated microgravity and ionizing radiation on expression profiles of mirna, lncrna, and mrna in human lymphoblastoid cells

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LIFE SCIENCES IN SPACE RESEARCH 2020年 24卷 1-8页

作者： Fu Hanjiang Su Fei Zhu Jie Zheng Xiaofei Ge Changhui Beijing Inst Radiat Med Dept Expt Hematol & Biochem 27 Taiping Rd Beijing 100850 Peoples R China

In space, multiple unique environmental factors, particularly microgravity and space radiation, pose a constant threat to astronaut health. Micrornas (mirnas) and long noncoding rnas (lncrnas) are functional rnas that play critical roles in regulating multiple cellular processes. To gain insight into the role of non-coding rnas in response to radiation and microgravity, we analyzed rna expression profiles in human lymphoblastoid TK6 cells incubated for 24 h under static or rotating conditions to stimulate microgravity in space, after 2-Gy gamma-ray irradiation. The expression of 14 lncrnas and 17 mrnas (differentially-expressed genes, DEGs) was found to be significantly downregulated under simulated microgravity conditions. In contrast, irradiation upregulated 55 lncrnas and 56 DEGs, whereas only one lncrna, but no DEGs, was downregulated. Furthermore, two mirnas, 70 lncrnas, and 87 DEGs showed significantly altered expression in response to simulated microgravity after irradiation, and these changes were independently induced by irradiation and simulated microgravity. GO enrichment and KEGG pathway analyses indicated that the associated target genes showed similar patterns to the noncoding rnas and were suggested to be involved in the immune/inflammatory response including LPS/TLR, TNF, and NF-kappa B signaling pathways. However, synergistic effects on rna expression and cellular responses were also observed with a combination of simulated microgravity and irradiation based on microarray and RT-PCR analysis. Together, our results indicate that simulated microgravity and irradiation additively alter expression patterns but synergistically modulate the expression levels of rnas and their target genes in human lymphoblastoid cells.

关键词： Human lymphoblastoid Irradiation long-noncoding rna microrna Simulated microgravity

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Identification of male infertility-related long non-coding rnas and their functions based on a competing endogenous rna network

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JOUrnaL OF INTErnaTIONAL MEDICAL RESEARCH 2020年第10期48卷 300060520961277-300060520961277页

作者： Zhou, Zuo Wang, Bing Hosp Zibo City Dept Obstet Maternal & Child Hlth Zibo Shandong Peoples R China Hosp Zibo City Ctr Reprod Med Maternal & Child Hlth 11 Xingyuan East Rd Zibo Shandong Peoples R China

Objective To identify male infertility-related long non-coding (lnc)rnas and an lncrna-related competing endogenous (ce)rna network. Methods Expression data including 13 normospermic and eight teratozoospermic samples from postmortem donors were downloaded from the GEO database (GSE6872). The limma R package was used to discriminate dysregulated lncrna and micro (m)rna profiles. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of differentially expressed (DE) mrnas were performed using the clusterProfiler R package. The cerna network of dysregulated genes was visualized by Cytoscape. Results A total of 101 DE lncrnas and 1722 mrnas were identified as male infertility-specific rnas with thresholds of |log(2)FoldChange| >2.0 and adjustedP-value <0.05. GO and KEGG pathways were analyzed for DE mrnas. Gene set enrichment analysis revealed that DE genes were enriched in embryonic skeletal system development and cytokine-cytokine receptor interactions. A cerna network was constructed with 26 key lncrnas, 33 micrornas, and 133 mrnas. DE lncrnas in male sterility were mainly associated with transferring phosphorus-containing groups and complexes of histone methyltransferases, methyltransferases, PcG proteins, and serine/threonine protein kinases. Conclusion This provides a novel perspective to study lncrna-related cerna networks in male infertility and assist in identifying new potential biomarkers for diagnostic purposes.

关键词： Male infertility competing endogenous rna long-noncoding rna gene set enrichment analysis differential expression gene ontology Kyoto Encyclopedia of Genes and Genomes

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SENCR stabilizes vascular endothelial cell adherens junctions through interaction with CKAP4

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2019年第2期116卷 546-555页

作者： Lyu, Qing Xu, Suowen Lyu, Yuyan Choi, Mihyun Christie, Christine K. Slivano, Orazio J. Rahman, Arshad Jin, Zheng-Gen long, Xiaochun Xu, Yawei Miano, Joseph M. Univ Rochester Sch Med & Dent Aab Cardiovasc Res Inst Rochester NY 14642 USA Tongji Univ Sch Med Shanghai Peoples Hosp 2 Dept Cardiol Shanghai 200072 Peoples R China Albany Med Coll Dept Mol & Cellular Physiol Albany NY 12208 USA Univ Rochester Sch Med & Dent Dept Pediat Rochester NY 14642 USA

SENCR is a human-specific, vascular cell-enriched long-noncoding rna (lncrna) that regulates vascular smooth muscle cell and endothelial cell (EC) phenotypes. The underlying mechanisms of action of SENCR in these and other cell types is unknown. Here, levels of SENCR rna are shown to be elevated in several differentiated human EC lineages subjected to laminar shear stress. Increases in SENCR rna are also observed in the laminar shear stress region of the adult aorta of humanized SENCR-expressing mice, but not in disturbed shear stress regions. SENCR loss-of-function studies disclose perturbations in EC membrane integrity resulting in increased EC permeability. Biotiny-lated rna pull-down and mass spectrometry establish an abundant SENCR-binding protein, cytoskeletal-associated protein 4 (CKAP4);this ribonucleoprotein complex was further confirmed in an rna immuno-precipitation experiment using an antibody to CKAP4. Structure-function studies demonstrate a noncanonical rna-binding domain in CKAP4 that binds SENCR. Upon SENCR knockdown, increasing levels of CKAP4 protein are detected in the EC surface fraction. Furthermore, an interaction between CKAP4 and CDH5 is enhanced in SENCR-depleted EC. This heightened association appears to destabilize the CDH5/CTNND1 complex and augment CDH5 internalization, resulting in impaired adherens junctions. These findings support SENCR as a flow-responsive lncrna that promotes EC adherens junction integrity through physical association with CKAP4, thereby stabilizing cell membrane-bound CDH5.

关键词： long-noncoding rna endothelial cell shear stress adherens junction

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Epigenetic Components of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Uncover Potential Transposable Element Activation

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CLINICAL THERAPEUTICS 2019年第4期41卷 675-698页

作者： Almenar-Perez, Eloy Ovejero, Tamara Sanchez-Fito, Teresa Espejo, Jose A. Nathanson, Lubov Oltra, Elisa Univ Catolica Valencia San Vicente Martir Escuela Doctorado Valencia Spain Univ Catolica Valencia San Vicente Martir Sch Med Valencia 46001 Spain Univ Catolica Valencia San Vicente Martir Sch Expt Sci Valencia Spain Nova Southeastern Univ Kiran C Patel Coll Osteopath Med Ft Lauderdale FL 33314 USA Nova Southeastern Univ Inst Neuro Immune Med Ft Lauderdale FL 33314 USA Ctr Invest Principe Felipe Unidad Mixta CIPF UCV Valencia Spain

Purpose: Studies to determine epigenetic changes associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remain scarce;however, current evidence clearly shows that methylation patterns of genomic DNA and noncoding rna profiles of immune cells differ between patients and healthy subjects, suggesting an active role of these epigenetic mechanisms in the disease. The present study compares and contrasts the available ME/CFS epigenetic data in an effort to evidence overlapping pathways capable of explaining at least some of the dysfunctional immune parameters linked to this disease. Methods: A systematic search of the literature evaluating the ME/CFS epigenome landscape was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Differential DNA methylation and noncoding rna differential expression patterns associated with ME/CFS were used to screen for the presence of transposable elements using the Dfam browser, a search program nurtured with the Repbase repetitive sequence database and the RepeatMasker annotation tool. Findings: Unexpectedly, particular associations of transposable elements and ME/CFS epigenetic hallmarks were uncovered. A model for the disease emerged involving transcriptional induction of endogenous dormant transposons and structured cellular rna interactions, triggering the activation of the innate immune system without a concomitant active infection. (C) 2019 Elsevier Inc. All rights reserved.

关键词： epigenetic long-noncoding rna microrna myalgic encephalomyelitis/chronic fatigue syndrome retrotransposon transposable elements

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Expanding the horizon of EV-rnas: Lncrnas in EVs as biomarkers for disease pathways

Extracellular vesicle

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Extracellular vesicle 2023年 2卷 100025页

作者： Michail Spanos Priyanka Gokulnath Emeli Chatterjee Guoping Li Dimitrios Varrias Saumya Das Cardiovascular Research Center Massachusetts General Hospital and Harvard Medical School Boston MA USA. Albert Einstein College of Medicine/Jacobi Medical Center The Bronx NY USA.

Extracellular vesicles (EVs) are membrane-bound nanoparticles with different types of cargo released by cells and postulated to mediate functions such as intercellular communications. Recent studies have shown that long non-coding rnas (lncrnas) or their fragments are present as cargo within EVs. Lncrnas are a heterogeneous group of rna species with a length exceeding 200 nucleotides with diverse functions in cells based on their localization. While lncrnas are known for their important functions in cellular regulation, their presence and role in EVs have only recently been explored. While certain studies have observed EV-lncrnas to be tissue-and disease-specific, it remains to be determined whether or not this is a global observation. Nonetheless, these molecules have demonstrated promising potential to serve as new diagnostic and prognostic biomarkers. In this review, we critically evaluate the role of EV-derived lncrnas in several prevalent diseases, including cancer, cardiovascular diseases, and neurodegenerative diseases, with a specific focus on their role as biomarkers.

关键词： Cancer Cardiovascular disease Extracellular vesicles long-noncoding rna Neurological disease

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