Long intergenic noncoding RNAs in cardiovascular diseases: Challenges and strategies for physiological studies and translation.
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ABSTRACT:
SUBMITTER: Zhang X
PROVIDER: S-EPMC7307970 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
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Project description:The new millennium heralds an unanticipated surge of genomic information, most notably an expansive class of long noncoding RNAs (lncRNAs). These transcripts, which now outnumber all protein-coding genes, often exhibit the same characteristics as mRNAs (RNA polymerase II-dependent, 5' methyl-capped, multiexonic, polyadenylated); yet, they do not encode for stable, well-conserved proteins. Elucidating the function of all relevant lncRNAs in heart, vasculature, lung, and blood is essential for generating a complete interactome in these tissues. This is particularly evident because an increasing number of investigators perform RNA-sequencing experiments where, typically, annotated lncRNAs exhibit impressive changes in gene expression. How does one go about evaluating an lncRNA when the sequence of the transcript lends no insight into how it may function within a cell type? Here, we provide a brief overview for the rational study of lncRNAs.
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Project description:Cardiovascular diseases (CVDs) remain the world's leading cause of death. Cardiomyocyte autophagy helps maintain normal metabolism and functioning of the heart. Importantly, mounting evidence has revealed that autophagy plays a dual role in CVD pathology. Under physiological conditions, moderate autophagy maintains cell metabolic balance by degrading and recycling damaged organelles and proteins, and it promotes myocardial survival, but excessive or insufficient autophagy is equally deleterious and contributes to disease progression. Noncoding RNAs (ncRNAs) are a class of RNAs transcribed from the genome, but most ncRNAs do not code for functional proteins. In recent years, increasingly, various ncRNAs have been identified, and they play important regulatory roles in the physiological and pathological processes of organisms, as well as in autophagy. Thus, determining whether ncRNA-regulated autophagy plays a protective role in CVDs or promotes their progression can help us to develop ncRNAs as therapeutic targets in autophagy-related CVDs. In this review, we briefly summarize the regulatory roles of several important ncRNAs, including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), in the autophagy of various CVDs to provide a theoretical basis for the etiology and pathogenesis of CVDs and develop novel therapies to treat CVDs.
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Project description:Long noncoding RNAs (lncRNAs) are involved in many physiological and pathological processes, such as development, aging, immunity, and cancer. Mechanistically, lncRNAs exert their functions through interaction with proteins, genomic DNA, and other RNA, leading to transcriptional and post-transcriptional regulation of gene expression, either in cis or in trans; it is often difficult to distinguish between these two regulatory mechanisms. A variety of approaches, including RNA interference, antisense oligonucleotides, CRISPR-based methods, and genetically engineered mouse models, have yielded abundant information about lncRNA functions and underlying mechanisms, albeit with many discrepancies. In this review, we elaborate on the challenges in ascribing functions to lncRNAs based on the features of lncRNAs, including the genomic location, copy number, domain structure, subcellular localization, stability, evolution, and expression pattern. We also describe a framework for the investigation of lncRNA functions and mechanisms of action. Rigorous characterization of cancer-implicated lncRNAs is critical for the identification of bona fide anticancer targets.
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Project description:BackgroundOver 10,000 long intergenic non-coding RNAs (lincRNAs) have been identified in the human genome. Some have been well characterized and known to participate in various stages of gene regulation. In the post-transcriptional process, another class of well-known small non-coding RNA, or microRNA (miRNA), is very active in inhibiting mRNA. Though similar features between mRNA and lincRNA have been revealed in several recent studies, and a few isolated miRNA-lincRNA relationships have been observed. Despite these advances, the comprehensive miRNA regulation pattern of lincRNA has not been clarified.MethodsIn this study, we investigated the possible interaction between the two classes of non-coding RNAs. Instead of using the existing long non-coding database, we employed an ab initio method to annotate lincRNAs expressed in a group of normal breast tissues and breast tumors.ResultsApproximately 90 lincRNAs show strong reverse expression correlation with miRNAs, which have at least one predicted target site presented. These target sites are statistically more conserved than their neighboring genetic regions and other predicted target sites. Several miRNAs that target to these lincRNAs are known to play an essential role in breast cancer.ConclusionSimilar to inhibiting mRNAs, miRNAs show potential in promoting the degeneration of lincRNAs. Breast-cancer-related miRNAs may influence their target lincRNAs resulting in differential expression in normal and malignant breast tissues. This implies the miRNA regulation of lincRNAs may be involved in the regulatory process in tumor cells.
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Project description:Most of the eukaryotic genome is pervasively transcribed, yielding hundreds to thousands of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), some of which are well conserved during evolution. Functions have been described for a few lncRNAs and circRNAs but remain elusive for most. Both classes of RNAs play regulatory roles in translation by interacting with messenger RNAs (mRNAs), microRNAs (miRNAs), or mRNA-binding proteins (RBPs), thereby modulating translation in trans Moreover, although initially defined as noncoding, a number of lncRNAs and circRNAs have recently been reported to contain functional open reading frames (ORFs). Here, we review current understanding of the roles played by lncRNAs and circRNAs in protein synthesis and discuss challenges and open questions in the field.
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Project description:Long intergenic noncoding RNAs (lincRNAs) have been suggested as playing important roles in human gene regulation. The majority of annotated human lincRNAs include multiple exons and are alternatively spliced. However, the connections between alternative RNA splicing (AS) and the functions/regulations of lincRNAs have remained elusive. In this study, we compared the sequence evolution and biological features between single-exonic lincRNAs and multi-exonic lincRNAs (SELs and MELs, respectively) that were present only in the hominoids (hominoid-specific) or conserved in primates (primate-conserved). The MEL exons were further classified into alternatively spliced exons (ASEs) and constitutively spliced exons (CSEs) for evolutionary analyses. Our results indicate that SELs and MELs differed significantly from each other. Firstly, in hominoid-specific lincRNAs, MELs (both CSEs and ASEs) evolved slightly more rapidly than SELs, which evolved approximately at the neutral rate. In primate-conserved lincRNAs, SELs and ASEs evolved slightly more slowly than CSEs and neutral sequences. The evolutionary path of hominid-specific lincRNAs thus seemed to have diverged from that of their more ancestral counterparts. Secondly, both of the exons and transcripts of SELs were significantly longer than those of MELs, and this was probably because SEL transcripts were more resistant to RNA splicing than MELs. Thirdly, SELs were physically closer to coding genes than MELs. Fourthly, SELs were more widely expressed in human tissues than MELs. These results suggested that SELs and MELs represented two biologically distinct groups of genes. In addition, the SEL-MEL and ASE-CSE differences implied that splicing might be important for the functionality or regulations of lincRNAs in primates.
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Project description:Long noncoding RNAs (lncRNAs) have emerged as important regulators of many biological processes, including embryogenesis and development. To provide a systematic analysis of lncRNAs expressed during chicken embryogenesis, we used Iso-Seq and RNA-Seq to identify potential lncRNAs at embryonic stages from d 1 to d 8 of incubation: sequential stages covering gastrulation, somitogenesis, and organogenesis. The data characterized an expanded landscape of lncRNAs, yielding 45,410 distinct lncRNAs (31,282 genes). Amongst these, a set of 13,141 filtered intergenic lncRNAs (lincRNAs) transcribed from 9803 lincRNA gene loci, of which, 66.5% were novel, were further analyzed. These lincRNAs were found to share many characteristics with mammalian lincRNAs, including relatively short lengths, fewer exons, lower expression levels, and stage-specific expression patterns. Functional studies motivated by "guilt-by-association" associated individual lincRNAs with specific GO functions, providing an important resource for future studies of lincRNA function. Most importantly, a weighted gene co-expression network analysis suggested that genes of the brown module were specifically associated with the day 2 stage. LincRNAs within this module were co-expressed with proteins involved in hematopoiesis and lipid metabolism. This study presents the systematic identification of lincRNAs in developing chicken embryos and will serve as a powerful resource for the study of lincRNA functions.
| S-EPMC8170422 | biostudies-literature
Project description:ObjectiveTranscriptome profiling of human tissues has revealed thousands of long intergenic noncoding RNAs (lincRNAs) at loci identified through large-scale genome-wide studies for complex cardiometabolic traits. This raises the question of whether genetic variation at nonconserved lincRNAs has any systematic association with complex disease, and if so, how different this pattern is from conserved lincRNAs. We evaluated whether the associations between nonconserved lincRNAs and 8 complex cardiometabolic traits resemble or differ from the pattern of association for conserved lincRNAs. Approach and Results: Our investigation of over 7000 lincRNA annotations from GENCODE Release 33-GRCh38.p13 for complex trait genetic associations leveraged several large, established meta-analyses genome-wide association study summary data resources, including GIANT (Genetic Investigation of Anthropometric Traits), UK Biobank, GLGC (Global Lipids Genetics Consortium), Cardiogram (Coronary Artery Disease Genome Wide Replication and Meta-Analysis), and DIAGRAM (Diabetes Genetics Replication and Meta-Analysis)/DIAMANTE (Diabetes Meta-Analysis of Trans-Ethnic Association Studies). These analyses revealed that (1) nonconserved lincRNAs associate with a range of cardiometabolic traits at a rate that is generally consistent with conserved lincRNAs; (2) these findings persist across different definitions of conservation; and (3) overall across all cardiometabolic traits, approximately one-third of genome-wide association study-associated lincRNAs are nonconserved, and this increases to about two-thirds using a more stringent definition of conservation.ConclusionsThese findings suggest that the traditional notion of conservation driving prioritization for functional and translational follow-up of complex cardiometabolic genomic discoveries may need to be revised in the context of the abundance of nonconserved long noncoding RNAs in the human genome and their apparent predilection to associate with complex cardiometabolic traits.
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Project description:Immune responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled, autoimmune diseases can occur. Autoimmune diseases (ADs) are a family of disorders characterized by the body's immune response being directed against its own tissues, with consequent chronic inflammation and tissue damage. Despite enormous efforts to identify new drug targets and develop new therapies to prevent and ameliorate AD symptoms, no definitive solutions are available today. Additionally, while substantial progress has been made in drug development for some ADs, most treatments only ameliorate symptoms and, in general, ADs are still incurable. Hundreds of genetic loci have been identified and associated with ADs by genome-wide association studies. However, the whole list of molecular factors that contribute to AD pathogenesis is still unknown. Noncoding (nc)RNAs, such as microRNAs, circular (circ)RNAs, and long noncoding (lnc)RNAs, regulate gene expression at different levels in various diseases, including ADs, and serve as potential drug targets as well as biomarkers for disease progression and response to therapy. In this review, we will focus on the potential roles and genetic regulation of ncRNA in four autoimmune diseases-systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes mellitus.
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Project description:Long intergenic noncoding RNAs (lincRNAs) are increasingly recognized as potential key regulators of heart development and related diseases, but their identities and functions remain elusive. In this study, we sought to identify and characterize the cardiac lincRNA transcriptome in the experimentally accessible zebrafish model by integrating bioinformatics analysis with experimental validation. By conducting genome-wide RNA sequencing profiling of zebrafish embryonic hearts, adult hearts, and adult muscle, we generated a high-confidence set of 813 cardiac lincRNA transcripts, 423 of which are novel. Among these lincRNAs, 564 are expressed in the embryonic heart, and 730 are expressed in the adult heart, including 2 novel lincRNAs, TCONS_00000891 and TCONS_00028686, which exhibit cardiac-enriched expression patterns in adult heart. Using a method similar to a fetal gene program, we identified 51 lincRNAs with differential expression patterns between embryonic and adult hearts, among which TCONS_00009015 responded to doxorubicin-induced cardiac stress. In summary, our genome-wide systematic identification and characterization of cardiac lincRNAs lays the foundation for future studies in this vertebrate model to elucidate crucial roles for cardiac lincRNAs during heart development and cardiac diseases.
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