lincRNA Expression Research Articles

LincRNA-p21 Promotes Cellular Senescence by Down-regulating the Wnt/β-catenin Pathway in MPP+-treated SH-SY5Y Cells.

Long intergenic non-coding RNA-p21 (lincRNA-p21) plays a critical role in various senescence-associated physiological and pathological conditions. We aimed to explore the senescence-associated effects of lincRNA-p21 in 1-methyl-4-phenylpyridinium (MPP+) treated neuroblastoma SH-SY5Y cell line as a therapeutic target. The RNA expression levels of lincRNA-p21, p53, p16, and telomere length were examined with reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The Telo TAGGG™ Telomerase PCR ELISA PLUS Kit was used to determine telomerase activity. Cellular viability was evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) assay. Western blot was performed to analyze β-catenin protein expression. Besides, oxidative stress was evaluated by J-aggregate-forming delocalized lipophilic cation, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine++ + iodide (JC‑1) stain, fluorescence spectrophotometry, colorimetric assay, and malondialdehyde (MDA) formation. This research demonstrated that MPP+ caused a distinct increase in the expression of LincRNA-p21 in SH-SY5Y cells. MPP+ induced cellular senescence with decreasing cellular proliferation and viability, increasing expression levels of senescence-associated makers such as genes p53 and p16, accompanied by significantly decreasing telomere length and telomerase activity. At the same time, these effects were abolished by silencing lincRNA-p21 with small interfering RNA (siRNA). On the contrary, β-catenin silencing contributes to reversing anti-senescent effects caused by lincRNA-p21 silencing. Moreover, modifying lincRNA-p21 exerted an anti-senescent influence depending on decreasing oxidant stress. Our study showed that in the treatment of MPP+, lincRNA-p21 might serve a role in the SH-SY5Y cell senescence by modulating the Wnt/β-catenin pathway, as well as increasing oxidant stress. Thus, trying to target lincRNA-p21 may have important therapeutic and practical implications for PD.

The Intergenic Type LncRNA (LINC RNA) Faces in Cancer with In Silico Scope and a Directed Lens to LINC00511: A Step toward ncRNA Precision.

Long intergenic non-coding RNA, is one type of lncRNA, exerting various cellular activities, as does ncRNA, including the regulation of gene expression and chromatin remodeling. The abnormal expression of lincRNAs can induce or suppress carcinogenesis. LincRNAs can regulate cancer progression through different mechanisms and are considered as potential drug targets. Genetic variations such as single nucleotide polymorphisms (SNPs) in lincRNAs may affect gene expression and messenger ribonucleic acid (mRNA) stability. SNPs in lincRNAs have been found to be associated with different types of cancer, as well. Specifically, LINC00511 has been known to promote the progression of multiple malignancies such as breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, and others, making it a promising cancer prognostic molecular marker. LincRNAs have been proved to be associated with different cancer types through various pathways. Herein, we performed a comprehensive literature and in silico databases search listing lncRNAs, lincRNAs including LINC00511, lncRNAs' SNPs, as well as LINC00511 SNPs in different cancer types, focusing on their role in various cancer types and mechanism(s) of action.

Transcription factors KANADI 1, MYB DOMAIN PROTEIN 44, and PHYTOCHROME INTERACTING FACTOR 4 regulate long intergenic noncoding RNAs expressed in Arabidopsis roots.

Thousands of long intergenic noncoding RNAs (lincRNAs) have been identified in plant genomes. While some lincRNAs have been characterized as important regulators in different biological processes, little is known about the transcriptional regulation for most plant lincRNAs. Through the integration of 8 annotation resources, we defined 6,599 high-confidence lincRNA loci in Arabidopsis (Arabidopsis thaliana). For lincRNAs belonging to different evolutionary age categories, we identified major differences in sequence and chromatin features, as well as in the level of conservation and purifying selection acting during evolution. Spatiotemporal gene expression profiles combined with transcription factor (TF) chromatin immunoprecipitation (ChIP) data were used to construct a TF-lincRNA regulatory network containing 2,659 lincRNAs and 15,686 interactions. We found that properties characterizing lincRNA expression, conservation, and regulation differ between plants and animals. Experimental validation confirmed the role of 3 TFs, KANADI 1, MYB DOMAIN PROTEIN 44, and PHYTOCHROME INTERACTING FACTOR 4, as key regulators controlling root-specific lincRNA expression, demonstrating the predictive power of our network. Furthermore, we identified 58 lincRNAs, regulated by these TFs, showing strong root cell type-specific expression or chromatin accessibility, which are linked with genome-wide association studies genetic associations related to root system development and growth. The multilevel genome-wide characterization covering chromatin state information, promoter conservation, and chromatin immunoprecipitation-based TF binding, for all detectable lincRNAs across 769 expression samples, permits rapidly defining the biological context and relevance of Arabidopsis lincRNAs through regulatory networks.

LincRNA_XR209691.3 could promote Bombyx mori nucleopolyhedrovirus replication by interacting with BmHSP70.

Long non-coding RNAs (lncRNAs), a class of transcripts exceeding 200 nucleotides and lacking protein coding potential, have been proven to play important roles in viral infection and host immunity. Bombyx mori nucleopolyhedrovirus (BmNPV) is an important pathogen, which causes the silkworm disease and leads to a huge challenge to the sericultural industry. At present, research on the roles of insect lncRNAs in host-virus interaction are relatively few. In this study, we explored the function of lincRNA_XR209691.3 that was significantly up-regulated in the silkworm fat body upon BmNPV infection. Firstly, the subcellular localization experiment confirmed that lincRNA_XR209691.3 was present in both the nucleus and cytoplasm. Enhancing the expression of lincRNA_XR209691.3 in BmN cells could promote the proliferation of BmNPV, while inhibition of lincRNA_XR209691.3 by RNA interference suppresses the proliferation of BmNPV. Combining RNA pull-down and mass spectrometry, we identified the host and BmNPV proteins that could interact with lincRNA_XR209691.3. Next, by using truncation experiment and RNA immunoprecipitation (RIP) assay, it was found that lincRNA_XR209691.3 could bind to the Actin domain of BmHSP70. Subsequently, overexpression of lncRNA_XR209691.3 in BmN cells promoted the expression of BmHSP70, while knockdown of BmHsp70 suppressed the replication of BmNPV. Based on the above results, it is speculated that lincRNA_XR209691.3 could promote the proliferation of BmNPV through interaction with BmHSP70, possibly by improving the stability of BmHSP70 and thereby enhancing the expression of BmHSP70. Our results shed light on the lncRNA function in insect-pathogen interactions and provide a new clue to elucidate the molecular mechanism of BmNPV infection.

Dysregulation of Long Intergenic Non-Coding RNA Expression in the Schizophrenia Brain.

Transcriptomic studies of the brains of schizophrenia (SZ) patients have produced abundant but largely inconsistent findings about the disorders pathophysiology. These inconsistencies might stem not only from the heterogeneous nature of the disorder, but also from the unbalanced focus on particular cortical regions and protein-coding genes. Compared to protein-coding transcripts, long intergenic non-coding RNA (lincRNA) display substantially greater brain region and disease response specificity, positioning them as prospective indicators of SZ-associated alterations. Further, a growing understanding of the systemic character of the disorder calls for a more systematic screening involving multiple diverse brain regions. We aimed to identify and interpret alterations of the lincRNA expression profiles in SZ by examining the transcriptomes of 35 brain regions. We measured the transcriptome of 35 brain regions dissected from eight adult brain specimens, four SZ patients, and four healthy controls, using high-throughput RNA sequencing. Analysis of these data yielded 861 annotated human lincRNAs passing the detection threshold. Of the 861 detected lincRNA, 135 showed significant region-dependent expression alterations in SZ (two-way ANOVA, BH-adjusted p 0.05) and 37 additionally showed significant differential expression between HC and SZ individuals in at least one region (post hoc Tukey test, p 0.05). For these 37 differentially expressed lincRNAs (DELs), 88% of the differences occurred in a cluster of brain regions containing axon-rich brain regions and cerebellum. Functional annotation of the DEL targets further revealed stark enrichment in neurons and synaptic transmission terms and pathways. Our study highlights the utility of a systematic brain transcriptome analysis relying on the expression profiles measured across multiple brain regions and singles out white matter regions as a prospective target for further SZ research.

Overexpression of long intergenic noncoding RNAs in bladder cancer: A new insight to cancer diagnosis

There is increasing evidence that show long noncoding RNAs including long intergenic noncoding RNAs (lincRNA) play a pivotal regulatory role in the biological processes. Differential expression of lincRNAs can be utilized for cancer diagnosis, prognosis, and targeted therapy. Little is known about their expressions in urothelial tumors. Concerning the potential role of lincRNAs in cancer development, we aimed to investigate the expression levels of LINC00958 and DNM3OS in bladder cancer. Fifty tumor and 50 adjacent non-tumor tissue samples along with their clinicopathological parameters were obtained from bladder cancer patients. Expressions of LINC00958 and DNM3OS were analyzed by Real-time PCR. ROC curve analysis was used to evaluate the diagnostic power of LINC0095 and DNM3OS for BC. Expression level of LINC00958 was considerably increased in cancerous tissues (P < 0.001) and in correlation with cigarette smoking (P = 0.043). DNM3OS expression was higher in the tumor tissues than normal tissues (P < 0.001) and showed a significant association with age (P = 0.038). By using the ROC curve, the diagnostic power of LINC00958 and DNM3OS transcript levels in bladder cancer were estimated to be 87% and 75%, respectively. Our findings offer some important intuitions into the oncogenic role of LINC00958 and DNM3OS in bladder cancer and suggest that they can be candidate biomarkers and may provide new approaches for the diagnosis and therapy if being validated in a larger sample size of clinical samples as well as functional studies.

Comprehensive Transcriptome Analysis of Follicles from Two Stages of the Estrus Cycle of Two Breeds Reveals the Roles of Long Intergenic Non-Coding RNAs in Gilts.

Simple SummaryThis study provides new perspectives about the roles of lincRNAs in the estrus expression of gilts, which is correlated with ovarian steroid hormone and follicular development. Follicular tissues from two stages of the estrus cycle of Large White and Mi gilts were used for RNA-seq. Some genes and lincRNAs related to estrus expression in pigs were discovered. PPI and ceRNA networks related to the estrus expression were constructed. These results suggest that the estrus expression may be affected by lincRNAs and their target genes.Visible and long-lasting estrus expression of gilts and sows effectively sends a mating signal. To reveal the roles of Long Intergenic Non-coding RNAs (lincRNAs) in estrus expression, RNA-seq was used to investigate the lincRNAs expression of follicular tissues from Large White gilts at diestrus (LD) and estrus (LE), and Chinese Mi gilts at diestrus (MD) and estrus (ME). Seventy-three differentially expressed lincRNAs (DELs) were found in all comparisons (LE vs. ME, LD vs. LE, and MD vs. ME comparisons). Eleven lincRNAs were differentially expressed in both LD vs. LE and MD vs. ME comparisons. Fifteen DELs were mapped onto the pig corpus luteum number Quantitative Trait Loci (QTL) fragments. A protein–protein interaction (PPI) network that involved estrus expression using 20 DEGs was then constructed. Interestingly, three predicted target DEGs (PTGs) (CYP19A1 of MSTRG.10910, CDK1 of MSTRG.10910 and MSTRG.23984, SCARB1 of MSTRG.1559) were observed in the PPI network. A competitive endogenous RNA (ceRNA) network including three lincRNAs, five miRNAs, and five genes was constructed. Our study provides new insight into the lincRNAs associated with estrus expression and follicular development in gilts.

Cis-regulated expression of non-conserved lincRNAs associates with cardiometabolic related traits.

Many complex disease risk loci map to intergenic regions containing long intergenic noncoding RNAs (lincRNAs). The majority of these is not conserved outside humans, raising the question whether genetically regulated expression of non-conserved and conserved lincRNAs has similar rates of association with complex traits. Here we leveraged data from the Genotype-Tissue Expression (GTEx) project and multiple public genome-wide association study (GWAS) resources. Using an established transcriptome-wide association study (TWAS) tool, FUSION, we interrogated the associations between cis-regulated expression of lincRNAs and multiple cardiometabolic traits. We found that cis-regulated expression of non-conserved lincRNAs had a strikingly similar trend of association with complex cardiometabolic traits as conserved lincRNAs. This finding challenges the conventional notion of conservation that has led to prioritization of conserved loci for functional studies and calls attention to the need to develop comprehensive strategies to study the large number of non-conserved human lincRNAs that may contribute to human disease.

CCCTC-binding factor is an upstream regulator of the pluripotency factor Oct4 and functions in active transcription of linc1253 and linc1356 genes in pluripotent cells

The embryonic stem cell- (ESC) specific transcription factor Oct4 is a well-known master regulator of pluripotency. The aim of this study was to identify upstream regulators of Oct4 and explore their functional link in regulating lincRNA expression in ESCs. By quantitative real-time PCR (RT-qPCR) analysis upon CCCTC-binding factor (CTCF) or Oct4 knockdown, here, we found that the chromatin insulator CTCF transcriptionally controls Oct4 gene expression in mouse ES cells. Furthermore, co-immunoprecipitation assays showed that CTCF physically interacts with Oct4. By analyzing CTCF and Oct4 ChIP-seq datasets in mouse ES cells and investigating their genomic occupancies, we demonstrated that CTCF and Oct4 share overlapping regulatory functions and are required for active transcription of long intergenic non-coding RNAs (lincRNAs) linc1253 and linc1356, which were reported to repress cellular lineage programs and maintain a pluripotent state. In summary, we propose an integrated model of transcriptional control mediated by CTCF, the master weaver of the genome, for the upstream regulation of Oct4-and ESC-associated genes. These results connect the chromatin insulator CTCF and the pluripotency factor Oct4 in the regulation of lincRNAs in pluripotent cells.

Linc8986 and linc0597 in plasma are novel biomarkers for systemic lupus erythematosus.

Despite increasing evidence that large intergenic non-coding RNAs (lincRNAs) are widely involved in human disease, the role of lincRNAs in the development of systemic lupus erythematosus (SLE) has remained largely elusive. The purpose of the present study was to investigate the expression of three lincRNAs (linc0597, linc8986 and linc7190) in the plasma of patients with SLE and their potential use as biomarkers for the diagnosis and treatment of SLE. Plasma samples were obtained from 54 patients with SLE, 24 patients with rheumatoid arthritis (RA), 24 patients with Sjogren's syndrome (SS) and 22 healthy controls. LincRNA expression levels were measured by reverse transcription-quantitative PCR. Compared with those in the healthy controls, the plasma levels of linc0597 and linc8986 were significantly increased in the patients with SLE (P<0.001), while the difference in the level of linc7190 was not significant (P=0.052). In addition, there was no significant difference in the levels of linc0597 and linc8986 among patients with RA, patients with SS and the healthy controls (P>0.05). Compared with patients with SLE without lupus nephritis (LN), the levels of linc0597 were significantly higher in patients with LN (P=0.044). For linc7190 and linc8986, there was no significant difference between patients with and without LN (P>0.05). Furthermore, complement component 3 (C3) levels were used to evaluate whether the expression of linc8986 and linc0597 is related to the activity of SLE. The results indicated that the levels of linc8986 and linc0597 were negatively correlated with the level of C3 (P<0.001 and P=0.004, respectively). Further analysis suggested that linc0597 and linc8986 were able to specifically identify patients with SLE and that a combination of linc0597 and linc8986 may improve the diagnostic accuracy. Therefore, the plasma levels of linc0597 and linc8986 may be suitable biomarkers for diagnosing SLE.

Identification of lncRNAs Differentially Expressed during Natural and Induced Estrus in Sheep

Background: The manipulation of the estrous cycle or induction of estrus is a commonly used technique in sheep industry. The goal of this study was to identify and characterize differences of non-coding RNAs (lincRNAs) expression between induced estrus and natural estrus using the BGISEQ-500 plat form in 7 Mongolian sheep, which will provide insights into the regulation mechanisms of lncRNAs in different reproduction mode of sheep. Methods: During the late spring, ovarian, pituitary, hypothalamic, pineal and uterine tissue samples were collected from four artificially induced estrus and three naturally estrus Mongolian sheep. Total RNA was extracted from the five tissues using TRIzol reagent (Invitrogen) and treated with DNase I following the manufacturer’s instructions. A total of 35 sheep samples were sequenced using the BGISEQ-500 plat form. Bioinformatics methods were used to analysis expression difference analysis between groups, SNP and InDel, alternative splicing, lncRNA’s miRNA precursor prediction, lncRNA target gene and family prediction. Result: 211 novel lncRNAs were systematically identified using RNA-Seq technology. Meanwhile, we found that there are diversifications of lncRNAs in induced estrus vs. nature estrus of ewes. Therefore, we predict that, under the action of exogenous hormones, many physiological processes of ewes may be affected to varying degrees through the change of LncRNA to a variety of pathways.

LINC00337 induces tumor development and chemoresistance to paclitaxel of breast cancer by recruiting M2 tumor-associated macrophages

BackgroundM2 tumor-associated macrophages are closely related to the progression and prognosis of breast cancer (BCa), and could be regulated by long intergenic non-coding RNAs (lincRNAs). Moreover, the differential expression of lincRNAs affects tumor resistance. This study focused on the potential involvement and mechanism of LINC00337 in BCa. MethodsThe expression of LINC00337 in BCa was detected by bioinformatics analysis and RT-qPCR. Cell viability and proliferation were analyzed by cell counting kit-8 (CCK-8) and clone formation assay. BCa cells were treated with different concentrations of paclitaxel (PAX) to determine the chemotherapy resistance of LINC00337. Tumor formation assay, Western blot, ELISA and immunohistochemistry were performed to determine the relationship between LINC00337 and PAX in vivo. Macrophages were induced to M2-like polarization, and then functional experiments (CCK-8, wound healing) and molecular experiments (ELISA, RT-qPCR, Western blot) were used to verify the role of LINC00337. ResultsLINC00337 was up-regulated in BCa. High-expressed LINC00337 accelerated viability and proliferation of BCa cells, improved the resistance of BCa cells to PAX, and accelerated tumor growth. Overexpressed LINC00337 up-regulated the expressions of M2 macrophage markers and M-CSF, and reduced the level of GM-CSF. PAX significantly reduced the viability of BCa cells and down-regulated LINC00337. Furthermore, the successfully induced M2 type macrophages to promote BCa cell activity, migration and EMT protein expression, and LINC00337 enhanced the effect of M2 type macrophages. ShLINC00337 had the opposite effect to overexpressed LINC00337. ConclusionLINC00337 accelerated the malignant phenotype of BCa cells and promoted chemoresistance to paclitaxel through M2-like macrophages.

Long Intergenic Non Coding RNA and MicroRNA Profiles of Pheochromocytoma and Paraganglioma as Prognostic Biomarkers

Abstract microRNAs (miRNAs) and long intergenic noncoding RNAs (lincRNAs) have been reported as important markers for many cancers. In search of new markers for the metastatic or aggressive phenotypes in the neuroendocrine tumor pheochromocytomas and paragangliomas (PCPG), we analyzed the non-coding transcriptome from patient gene expression data in The Cancer Genome Atlas. We used differential expression analysis and an elastic-net machine-learning model to identify miRNA and lincRNA transcriptomic signature specific to PCPG molecular subtypes. Similarly, miRNAs and lincRNAs specific to aggressive PCPGs were identified, and univariate and multivariate analysis were performed for identifying factors associated with metastasis-free survival. Upregulation of 13 lincRNAs and 4 miRNAs was found to be associated with aggressive/metastatic PCPGs. RT-PCR validation in tumor samples from PCPG patients confirmed the overexpression of 4 miRNAs and 4 lincRNAs in metastatic compared to non-metastatic PCPGs. Kaplan-Meier analysis identified 3 miRNAs and 5 lincRNAs as prognostic markers for metastasis-free survival of patients in PCPGs. In a multivariate Cox regression analysis combining these miRNA and lincRNA expression signatures with the previously identified clinically relevant parameters like SDHB germline mutation, ATRX somatic mutation, tumor location and hormone secretion phenotypes, we identified the miRNA miR-182 and lincRNA HIF1A-AS2 as independent predictors of poor metastasis-free survival. We formulated a risk-score model using multivariate analysis of lincRNA and miRNA expression profiles, presence of SDHB and ATRX mutations, tumor location, and hormone secretion phenotypes. Stratification of PCPG patients with this risk-score showed significant differences in metastasis-free survival.

RNA-Seq Implies Divergent Regulation Patterns of LincRNA on Spermatogenesis and Testis Growth in Goats.

Long intergenic non-coding RNAs (lincRNAs) regulate testicular development by acting on protein-coding genes. However, little is known about whether lincRNAs and protein-coding genes exhibit the same expression pattern in the same phase of postnatal testicular development in goats. Therefore, this study aimed to demonstrate the expression patterns and roles of lincRNAs during the postnatal development of the goat testis. Herein, the testes of Yiling goats with average ages of 0, 30, 60, 90, 120, 150, and 180 days postnatal (DP) were used for RNA-seq. In total, 20,269 lincRNAs were identified, including 16,931 novel lincRNAs. We identified seven time-specifically diverse lincRNA modules and six mRNA modules by weighted gene co-expression network analysis (WGCNA). Interestingly, the down-regulation of growth-related lincRNAs was nearly one month earlier than the up-regulation of spermatogenesis-related lincRNAs, while the down-regulation of growth-related protein-coding genes and the correspondent up-regulation of spermatogenesis-related protein-coding genes occurred at the same age. Then, potential lincRNA target genes were predicted. Moreover, the co-expression network of lincRNAs demonstrated that ENSCHIT00000000777, ENSCHIT00000002069, and ENSCHIT00000005076 were the key lincRNAs in the process of testis development. Our study discovered the divergent regulation patterns of lincRNA on spermatogenesis and testis growth, providing a fresh insight into age-biased changes in lincRNA expression in the goat testis.

Mutation of a major CG methylase alters genome-wide lncRNA expression in rice

Plant long non-coding RNAs (lncRNAs) function in diverse biological processes, and lncRNA expression is under epigenetic regulation, including by cytosine DNA methylation. However, it remains unclear whether 5-methylcytosine (5mC) plays a similar role in different sequence contexts (CG, CHG, and CHH). In this study, we characterized and compared the profiles of genome-wide lncRNA profiles (including long intergenic non-coding RNAs [lincRNAs] and long noncoding natural antisense transcripts [lncNATs]) of a null mutant of the rice DNA methyltransferase 1, OsMET1-2 (designated OsMET1-2−/−) and its isogenic wild type (OsMET1-2+/+). The En/Spm transposable element (TE) family, which was heavily methylated in OsMET1-2+/+, was transcriptionally de-repressed in OsMET1-2−/− due to genome-wide erasure of CG methylation, and this led to abundant production of specific lncRNAs. In addition, RdDM-mediated CHH hypermethylation was increased in the 5′-upstream genomic regions of lncRNAs in OsMET1-2−/−. The positive correlation between the expression of lincRNAs and that of their proximal protein-coding genes was also analyzed. Our study shows that CG methylation negatively regulates the TE-related expression of lncRNA and demonstrates that CHH methylation is also involved in the regulation of lncRNA expression.

LincRNA-immunity landscape analysis identifies EPIC1 as a regulator of tumor immune evasion and immunotherapy resistance.

Through an integrative analysis of the lincRNA expression and tumor immune response in 9,626 tumor samples across 32 cancer types, we developed a lincRNA-based immune response (LIMER) score that can predict the immune cells infiltration and patient prognosis in multiple cancer types. Our analysis also identified tumor-specific lincRNAs, including EPIC1, that potentially regulate tumor immune response in multiple cancer types. Immunocompetent mouse models and in vitro co-culture assays demonstrated that EPIC1 induces tumor immune evasion and resistance to immunotherapy by suppressing tumor cell antigen presentation. Mechanistically, lincRNA EPIC1 interacts with the histone methyltransferase EZH2, leading to the epigenetic silencing of IFNGR1, TAP1/2, ERAP1/2, and MHC-I genes. Genetic and pharmacological inhibition of EZH2 abolish EPIC1's immune-related oncogenic effect and its suppression of interferon-γ signaling. The EPIC1-EZH2 axis emerges as a potential mechanism for tumor immune evasion that can serve as therapeutic targets for immunotherapy.

Predicting lincRNA-Disease Association in Heterogeneous Networks Using Co-regularized Non-negative Matrix Factorization.

Long intergenic non-coding ribonucleic acids (lincRNAs) are critical regulators for many complex diseases, and identification of disease-lincRNA association is both costly and time-consuming. Therefore, it is necessary to design computational approaches to predict the disease-lincRNA associations that shed light on the mechanisms of diseases. In this study, we develop a co-regularized non-negative matrix factorization (aka Cr-NMF) to identify potential disease-lincRNA associations by integrating the gene expression of lincRNAs, genetic interaction network for mRNA genes, gene-lincRNA associations, and disease-gene associations. The Cr-NMF algorithm factorizes the disease-lincRNA associations, while the other associations/interactions are integrated using regularization. Furthermore, the regularization does not only preserve the topological structure of the lincRNA co-expression network, but also maintains the links “lincRNA → gene → disease.” Experimental results demonstrate that the proposed algorithm outperforms state-of-the-art methods in terms of accuracy on predicting the disease-lincRNA associations. The model and algorithm provide an effective way to explore disease-lncRNA associations.

MBRS-04. MEDULLOBLASTOMA DETECTION BY BLOOD TEST

INTRODUCTIONLong non coding RNAs (lincRNAs) are functionally defined as transcripts longer than 200 nucleotides in length with no protein coding potential. lincRNA involvement in human cancers etiology is being increasingly proved. Cancer-secreted long non-coding RNAs (lncRNAs) in exosomes are emerging mediators of cancer-host cross talk communication in tumor microenvironments. The ability to monitor and detect tumor markers in real time enables access to tumor biology and may allow highly personalized treatment for each patient. METHODS ANDRESULTSWe analyzed RNA sequencing of 64 Medulloblastoma samples and quantified the genome wide long non coding RNAs (lincRNA) expression levels. We identified a lincRNA that is distinctively highly expressed in group 4 (MB4). MB4 expression was further examined in microarray analysis on a larger cohort of medulloblastoma patient samples and a large cohort (n=1405) of patient samples that include normal brain and different brain tumor samples. MB4 proved to be specific and highly expressed in group 4 Medulloblastoma. MB4 was detected in the plasma of medulloblastoma patients with active disease, or subtotal resection. MB4 was not detected in patients that their tumors were resected. MB4 expression is not detected in the serum of medulloblastoma type SHH, penioblastoma, ewing sarcoma and neuroblastoma patients.CONCLUSIONSWe have found that MB4 lncRNA is a highly specific medulloblastoma tumor biomarker and is sensitive and noninvasive biomarker that can be quantified from a blood test. MB4 can be a good diagnostic marker, and in future both may also be a good target for therapy.

Developmental programming in human umbilical cord vein endothelial cells following fetal growth restriction

BackgroundFetal growth restriction (FGR) is associated with an increased susceptibility for various noncommunicable diseases in adulthood, including cardiovascular and renal disease. During FGR, reduced uteroplacental blood flow, oxygen and nutrient supply to the fetus are hypothesized to detrimentally influence cardiovascular and renal programming. This study examined whether developmental programming profiles, especially related to the cardiovascular and renal system, differ in human umbilical vein endothelial cells (HUVECs) collected from pregnancies complicated by placental insufficiency-induced FGR compared to normal growth pregnancies. Our approach, involving transcriptomic profiling by RNA-sequencing and gene set enrichment analysis focused on cardiovascular and renal gene sets and targeted DNA methylation assays, contributes to the identification of targets underlying long-term cardiovascular and renal diseases.ResultsGene set enrichment analysis showed several downregulated gene sets, most of them involved in immune or inflammatory pathways or cell cycle pathways. seven of the 22 significantly upregulated gene sets related to kidney development and four gene sets involved with cardiovascular health and function were downregulated in FGR (n = 11) versus control (n = 8). Transcriptomic profiling by RNA-sequencing revealed downregulated expression of LGALS1, FPR3 and NRM and upregulation of lincRNA RP5-855F14.1 in FGR compared to controls. DNA methylation was similar for LGALS1 between study groups, but relative hypomethylation of FPR3 and hypermethylation of NRM were present in FGR, especially in male offspring. Absolute differences in methylation were, however, small.ConclusionThis study showed upregulation of gene sets related to renal development in HUVECs collected from pregnancies complicated by FGR compared to control donors. The differentially expressed gene sets related to cardiovascular function and health might be in line with the downregulated expression of NRM and upregulated expression of lincRNA RP5-855F14.1 in FGR samples; NRM is involved in cardiac remodeling, and lincRNAs are correlated with cardiovascular diseases. Future studies should elucidate whether the downregulated LGALS1 and FPR3 expressions in FGR are angiogenesis-modulating regulators leading to placental insufficiency-induced FGR or whether the expression of these genes can be used as a biomarker for increased cardiovascular risk. Altered DNA methylation might partly underlie FPR3 and NRM differential gene expression differences in a sex-dependent manner.

Association between lincRNA expression and overall survival for patients with triple-negative breast cancer.

Long intergenic non-coding RNAs (lincRNAs) are increasingly recognized as important regulators for pathogenesis and/or prognosis of breast cancer, including triple-negative breast cancer (TNBC) subtype. However, few previous studies used RNA-sequencing (RNA-Seq) technology, and none included an independent replication. To systematically evaluate the association between expression of lincRNAs and TNBC survival, we examined lincRNA expression profiles in TNBC tissues using RNA-Seq data for 200 TNBC patients from the Shanghai Breast Cancer Survival Study (SBCSS) and Southern Community Cohort Study (SCCS). Twenty-five lincRNAs were found to be associated with overall survival (P < 0.05 and no significant heterogeneity across studies at Q statistic P > 0.1), and 61 lincRNAs were associated with disease-free survival (DFS). Among these, two lincRNAs (LINC01270 and LINC00449) were significantly associated with both worse overall survival and DFS and were expressed at significantly higher levels in tumor tissues compared with adjacent normal breast tissues (log2[Fold Change] > 0.5 and FDR < 0.05). We further evaluated the potential functions of LINC01270 and LINC00449 using in vitro functional experiments and found that siRNA-mediated knockdown of LINC01270 and LINC00449 expression significantly decreased cell viability, colony formation and cell migration ability in TNBC cells (P < 0.05). Evidence from observational studies and in vitro experiments indicates that LINC00449 and LINC01270 may be prognostic biomarkers for TNBC.