Browsing by Subject "Long non-coding RNA"
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Item Characterizing alternative splicing and long non-coding RNA with high-throughput sequencing technology(2018-10) Zhou, Ao; Wu, Huanmei; Liu, Yunlong; Janga, Sarath C.; Liu, XiaowenSeveral experimental methods has been developed for the study of the central dogma since late 20th century. Protein mass spectrometry and next generation sequencing (including DNA-Seq and RNA-Seq) forms a triangle of experimental methods, corresponding to the three vertices of the central dogma, i.e., DNA, RNA and protein. Numerous RNA sequencing and protein mass spectrometry experiments has been carried out in attempt to understand how the expression change of known genes affect biological functions in various of organisms, however, it has been once overlooked that the result data of these experiments are in fact holograms which also reveals other delicate biological mechanisms, such as RNA splicing and the expression of long non-coding RNAs. In this dissertation, we carried out five studies based on high-throughput sequencing data, in an attempt to understand how RNA splicing and differential expression of long non-coding RNAs is associated biological functions. In the first two studies, we identified and characterized 197 stimulant induced and 477 developmentally regulated alternative splicing events from RNA sequencing data. In the third study, we introduced a method for identifying novel alternative splicing events that were never documented. In the fourth study, we introduced a method for identifying known and novel RNA splicing junctions from protein mass spectrometry data. In the fifth study, we introduced a method for identifying long non-coding RNAs from poly-A selected RNA sequencing data. Taking advantage of these methods, we turned RNA sequencing and protein mass spectrometry data into an information gold mine of splicing and long non-coding RNA activities.Item Cholangiocarcinoma: novel therapeutic targets(Taylor & Francis, 2020-04) Sato, Keisaku; Glaser, Shannon; Alvaro, Domenico; Meng, Fanyin; Francis, Heather; Alpini, Gianfranco; Medicine, School of MedicineIntroduction: Cholangiocarcinoma (CCA) is a liver cancer derived from the biliary tree with a less than 30% five-year survival rate. Early diagnosis of CCA is challenging and treatment options are limited. Some CCA patients have genetic mutations and several therapeutic drugs or antibodies have been introduced to target abnormally expressed proteins. However, CCA is heterogeneous and patients often present with drug resistance which is attributed to multiple mutations or other factors. Novel approaches and methodologies for CCA treatments are in demand.Area covered: This review summarizes current approaches for CCA treatments leading to the development of novel therapeutic drugs or tools for human CCA patients. A literature search was conducted in PubMed utilizing the combination of the searched term 'cholangiocarcinoma' with other keywords such as 'miRNA', 'FGFR', 'immunotherapy' or 'microenvironment'. Papers published within 2015-2019 were obtained for reading.Expert opinion: Preclinical studies have demonstrated promising therapeutic approaches that target various cells or pathways. Recent studies have revealed that hepatic cells coordinate to promote CCA tumor progression in the tumor microenvironment, which may be a new therapeutic target. Although further studies are required, novel therapeutic tools such as extracellular vesicles could be utilized to manage CCA and its microenvironment.Item LncRNA AK054921 and AK128652 are potential serum biomarkers and predictors of patient survival with alcoholic cirrhosis(Wiley, 2017-08) Yang, Zhihong; Ross, Ruth A.; Zhao, Shi; Tu, Wanzhu; Liangpunsakul, Suthat; Wang, Li; Medicine, School of MedicineBackground: Alcoholic liver disease (ALD) is one of the leading causes of chronic liver disease. Recent studies have demonstrated the roles of long noncoding RNAs (lncRNAs) in the pathogenesis of several disease processes. However, the roles of lncRNAs in patients with ALD remain unexplored. Methods: Global profiling for human lncRNAs from peripheral blood RNA was performed in a well characterized cohort of healthy controls (HC, n=4), excessive drinkers without liver diseases (ED, n=4), and those with alcoholic cirrhosis with different severities (AC, n=12). The expression of unique lncRNA signatures were validated in a separate cohort of HC (n=17), ED (n=19), AC (n=48), and human liver tissues with ALD (n=19). Results: Detailed analysis of plasma lncRNAs in AC subjects with different severities compared to HC identified 244 commonly up-regulated lncRNAs and 181 commonly down-regulated lncRNAs. We further validated top 20 most differentially up- and down-regulated lncRNAs in ED and AC as compared to HC and also determined the expression of selected lncRNAs in human liver tissues with or without AC. Among those lncRNAs, AK128652 and AK054921 were two of the most abundantly expressed lncRNAs in normal human plasma and liver, and their levels were significantly elevated in AC. The prognostic significance of AK128652 and AK054921 was determined in 48 subjects with AC; who were prospectively followed for 520 days. The expression of AK128652 and AK054921 was inversely associated with survival in patients with AC. Conclusions: LncRNAs AK054921 and AK128652 are potential biomarkers to predict the progression to ALD in those with excessive alcohol consumption and are predictors of survival with patients with alcoholic cirrhosis.Item LncRNA HBL1 is required for genome-wide PRC2 occupancy and function in cardiogenesis from human pluripotent stem cells(The Company of Biologists, 2021-07) Liu, Juli; Liu, Sheng; Han, Lei; Sheng, Yi; Zhang, Yucheng; Kim, Il-Man; Wan, Jun; Yang, Lei; Pediatrics, School of MedicinePolycomb repressive complex 2 (PRC2) deposits H3K27me3 on chromatin to silence transcription. PRC2 broadly interacts with RNAs. Currently, the role of the RNA-PRC2 interaction in human cardiogenesis remains elusive. Here, we found that human-specific heart brake lncRNA 1 (HBL1) interacted with two PRC2 subunits, JARID2 and EED, in human pluripotent stem cells (hPSCs). Loss of JARID2, EED or HBL1 significantly enhanced cardiac differentiation from hPSCs. HBL1 depletion disrupted genome-wide PRC2 occupancy and H3K27me3 chromatin modification on essential cardiogenic genes, and broadly enhanced cardiogenic gene transcription in undifferentiated hPSCs and later-on differentiation. In addition, ChIP-seq revealed reduced EED occupancy on 62 overlapped cardiogenic genes in HBL1−/− and JARID2−/− hPSCs, indicating that the epigenetic state of cardiogenic genes was determined by HBL1 and JARID2 at pluripotency stage. Furthermore, after cardiac development occurs, the cytosolic and nuclear fractions of HBL1 could crosstalk via a conserved ‘microRNA-1-JARID2’ axis to modulate cardiogenic gene transcription. Overall, our findings delineate the indispensable role of HBL1 in guiding PRC2 function during early human cardiogenesis, and expand the mechanistic scope of lncRNA(s) that cytosolic and nuclear portions of HBL1 could coordinate to orchestrate human cardiogenesis.Item Long Non-Coding RNA Expression Levels Modulate Cell-Type-Specific Splicing Patterns by Altering Their Interaction Landscape with RNA-Binding Proteins(MDPI, 2019-08-06) Porto, Felipe Wendt; Daulatabad, Swapna Vidhur; Janga, Sarath Chandra; BioHealth Informatics, School of Informatics and ComputingRecent developments in our understanding of the interactions between long non-coding RNAs (lncRNAs) and cellular components have improved treatment approaches for various human diseases including cancer, vascular diseases, and neurological diseases. Although investigation of specific lncRNAs revealed their role in the metabolism of cellular RNA, our understanding of their contribution to post-transcriptional regulation is relatively limited. In this study, we explore the role of lncRNAs in modulating alternative splicing and their impact on downstream protein-RNA interaction networks. Analysis of alternative splicing events across 39 lncRNA knockdown and wildtype RNA-sequencing datasets from three human cell lines-HeLa (cervical cancer), K562 (myeloid leukemia), and U87 (glioblastoma)-resulted in the high-confidence (false discovery rate (fdr) < 0.01) identification of 11,630 skipped exon events and 5895 retained intron events, implicating 759 genes to be impacted at the post-transcriptional level due to the loss of lncRNAs. We observed that a majority of the alternatively spliced genes in a lncRNA knockdown were specific to the cell type. In tandem, the functions annotated to the genes affected by alternative splicing across each lncRNA knockdown also displayed cell-type specificity. To understand the mechanism behind this cell-type-specific alternative splicing pattern, we analyzed RNA-binding protein (RBP)-RNA interaction profiles across the spliced regions in order to observe cell-type-specific alternative splice event RBP binding preference. Despite limited RBP binding data across cell lines, alternatively spliced events detected in lncRNA perturbation experiments were associated with RBPs binding in proximal intron-exon junctions in a cell-type-specific manner. The cellular functions affected by alternative splicing were also affected in a cell-type-specific manner. Based on the RBP binding profiles in HeLa and K562 cells, we hypothesize that several lncRNAs are likely to exhibit a sponge effect in disease contexts, resulting in the functional disruption of RBPs and their downstream functions. We propose that such lncRNA sponges can extensively rewire post-transcriptional gene regulatory networks by altering the protein-RNA interaction landscape in a cell-type-specific manner.Item Long Non-coding RNA in Liver Metabolism and Disease: Current Status(Elsevier, 2017-09) Zhao, Yulan; Wu, Jianguo; Liangpunsakul, Suthat; Wang, Li; Medicine, School of MedicineLong non-coding RNAs (lncRNAs) are comprised of RNA transcripts exceeding 200 nucleotides in length but lacking identifiable open reading frames (with rare exceptions). Herein, we highlight emerging evidence demonstrating that lncRNAs are critical regulators of liver metabolic function and diseases. We summarize current knowledges about dysregulated lncRNAs and outline the underlying molecular mechanisms by which lncRNAs control hepatic lipid ad glucose metabolism, as well as cholestatic liver disease. lncLSTR, Lnc18q22.2, SRA, HULC, MALAT1, lncLGR, MEG3, and H19, lncHR1, lnc-HC, APOA1-AS, DYNLRB2-2, and LeXis are included in the discussion.Item Long Non-coding RNAs in Prostate Cancer with Emphasis on Second Chromosome Locus Associated with Prostate-1 Expression(Frontiers Media, 2017-12-12) Cimadamore, Alessia; Gasparrini, Silvia; Mazzucchelli, Roberta; Doria, Andrea; Cheng, Liang; Lopez-Beltran, Antonio; Santoni, Matteo; Scarpelli, Marina; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of MedicineLong non-coding RNAs (lncRNAs) are a class of RNA with transcripts longer than 200 nucleotides that lack functional open reading frames. They play various roles in human carcinoma, such as dysregulating gene expression in prostate cancer (PCa), which results in cancer initiation, development, and progression. The non-coding RNA SChLAP1 (second chromosome locus associated with prostate-1) is highly expressed in approximately 25% of PCas with higher prevalence in metastatic compared to localized PCa. Its expression is detectable non-invasively in PCa patient urine samples. Experimental data suggest that targeting SChLAP1 may represent a novel therapeutic application in PCa. This contribution focuses on the role of lncRNAs SChLAP1 expression in PCa diagnosis and prognosis.Item Multidimensional Mechanistic Spectrum of Long Non-coding RNAs in Heart Development and Disease(Frontiers Media, 2021-09-16) Han, Lei; Yang, Lei; Pediatrics, School of MedicineWith the large-scale genome-wide sequencing, long non-coding RNAs (lncRNAs) have been found to compose of a large portion of the human transcriptome. Recent studies demonstrated the multidimensional functions of lncRNAs in heart development and disease. The subcellular localization of lncRNA is considered as a key factor that determines lncRNA function. Cytosolic lncRNAs mainly regulate mRNA stability, mRNA translation, miRNA processing and function, whereas nuclear lncRNAs epigenetically regulate chromatin remodeling, structure, and gene transcription. In this review, we summarize the molecular mechanisms of cytosolic and nuclear lncRNAs in heart development and disease separately, and emphasize the recent progress to dictate the crosstalk of cytosolic and nuclear lncRNAs in orchestrating the same biological process. Given the low evolutionary conservation of most lncRNAs, deeper understanding of human lncRNA will uncover a new layer of human regulatory mechanism underlying heart development and disease, and benefit the future clinical treatment for human heart disease.Item Transcriptome-Wide Methods for functional and Structural Annotation of Long Non-Coding RNAs(2023-05) Daulatabad, Swapna Vidhur; Janga, Sarath Chandra; Reda, Khairi; Yan, Jingwen; Ye, YuzhenNon-coding RNAs across the genome have been associated with various biological processes, ranging from regulation of splicing to remodeling of chromatin. Amongst the repertoire of non-coding sequences lies a critical species of RNAs called long non-coding RNAs (lncRNAs). LncRNAs significantly contribute to a large spectrum of human phenotypes, including cancers, Heart failure, Diabetes, and Alzheimer’s disease. This dissertation emphasizes the need to characterize the functional role of lncRNAs to improve our understanding of human diseases. This work consolidates a resource from multiple computational genomics and natural language processing-based approaches to advance our ability to functionally annotate hundreds of lncRNAs and their interactions, providing a one-stop lncRNA functional annotation and dynamic interaction network and multi-facet omics data visualization platform. RNA interactions are vital in various cellular processes, from transcription to RNA processing. These interactions dictate the functional scope of the RNA. However, the multifaceted functional nature of RNA stems from its ability to form secondary structures. Therefore, this work establishes a computational method to characterize RNA secondary structure by integrating SHAPE-seq and long-read sequencing to enhance further our understanding of RNA structure in modulating the post-transcriptional regulatory processes and deciphering the influence at several layers of biological features, ranging from structure composition to consequent protein occupancy. This study will potentially impact the research community by providing methods, web interfaces, and computational pipelines, improving our functional understanding of long non-coding RNAs. This work also provides novel integration methods of technologies like Oxford Nanopore-based long-read sequencing, RNA structure-probing methods, and machine learning. The approaches developed in this dissertation are scalable and adaptable to investigate further the functional and regulatory role of RNA and its structure. Overall, this study accelerates the development of RNA-based diagnostics and the identification of therapeutic targets in human disease.Item Up-Regulation of the Long Noncoding RNA X-Inactive-Specific Transcript and the Sex Bias in Pulmonary Arterial Hypertension(Elsevier, 2021) Qin, Shanshan; Predescu, Dan; Carman, Brandon; Patel, Priyam; Chen, Jiwang; Kim, Miran; Lahm, Tim; Geraci, Mark; Predescu, Sanda A.; Medicine, School of MedicinePulmonary arterial hypertension (PAH) is a sex-biased disease. Increased expression and activity of the long-noncoding RNA X-inactive-specific transcript (Xist), essential for X-chromosome inactivation and dosage compensation of X-linked genes, may explain the sex bias of PAH. The present studies used a murine model of plexiform PAH, the intersectin-1s (ITSN) heterozygous knockout (KOITSN+/-) mouse transduced with an ITSN fragment (EHITSN) possessing endothelial cell proliferative activity, in conjunction with molecular, cell biology, biochemical, morphologic, and functional approaches. The data demonstrate significant sex-centered differences with regard to EHITSN-induced alterations in pulmonary artery remodeling, lung hemodynamics, and p38/ETS domain containing protein/c-Fos signaling, altogether leading to a more severe female lung PAH phenotype. Moreover, the long-noncoding RNA-Xist is up-regulated in the lungs of female EHITSN-KOITSN+/- mice compared with that in female wild-type mice, leading to sex-specific modulation of the X-linked gene ETS domain containing protein and its target, two molecular events also characteristic to female human PAH lung. More importantly, cyclin A1 expression in the S and G2/M phases of the cell cycle of synchronized pulmonary artery endothelial cells of female PAH patients is greater versus controls, suggesting functional hyperproliferation. Thus, Xist up-regulation leading to female pulmonary artery endothelial cell sexual dimorphic behavior may provide a better understanding of the origin of sex bias in PAH. Notably, the EHITSN-KOITSN+/- mouse is a unique experimental animal model of PAH that recapitulates most of the sexually dimorphic characteristics of human disease.