The Intertwining of Transposable Elements and Non-Coding RNAs

Growing evidence shows a close association of transposable elements (TE) with non-coding RNAs (ncRNA), and a significant number of small ncRNAs originate from TEs. Further, ncRNAs linked with TE sequences participate in a wide-range of regulatory functions. Alu elements in particular are critical players in gene regulation and molecular pathways. Alu sequences embedded in both long non-coding RNAs (lncRNA) and mRNAs form the basis of targeted mRNA decay via short imperfect base-pairing. Imperfect pairing is prominent in most ncRNA/target RNA interactions and found throughout all biological kingdoms. The piRNA-Piwi complex is multifunctional, but plays a major role in protection against invasion by transposons. This is an RNA-based genetic immune system similar to the one found in prokaryotes, the CRISPR system. Thousands of long intergenic non-coding RNAs (lincRNAs) are associated with endogenous retrovirus LTR transposable elements in human cells. These TEs can provide regulatory signals for lincRNA genes. A surprisingly large number of long circular ncRNAs have been discovered in human fibroblasts. These serve as “sponges” for miRNAs. Alu sequences, encoded in introns that flank exons are proposed to participate in RNA circularization via Alu/Alu base-pairing. Diseases are increasingly found to have a TE/ncRNA etiology. A single point mutation in a SINE/Alu sequence in a human long non-coding RNA leads to brainstem atrophy and death. On the other hand, genomic clusters of repeat sequences as well as lncRNAs function in epigenetic regulation. Some clusters are unstable, which can lead to formation of diseases such as facioscapulohumeral muscular dystrophy. The future may hold more surprises regarding diseases associated with ncRNAs andTEs.     

Comprehensive Transcriptome Analysis of Hair Follicle Morphogenesis Reveals That lncRNA-H19 Promotes Dermal Papilla Cell Proliferation through the Chi-miR-214-3p/β-Catenin Axis in Cashmere Goats

Cashmere is initiated and develops in the fetal stages and the number and density of secondary hair follicles (SHFs) determine cashmere production and quality. Growing evidence indicates that both microRNA (miRNA) and long non-coding RNA (lncRNA) play an indispensable role in hair follicle (HF) growth and development. However, little is known about miRNAs, lncRNAs, and their functions as well as their interactions during cashmere initiation and development. Here, based on lncRNA and miRNA high-throughput sequencing and bioinformatics analysis, we identified 10,485 lncRNAs, 40,639 mRNAs, and 605 miRNAs in cashmere goat skin during HF induction, organogenesis, and cytodifferentiation stages. Among them, 521 lncRNAs, 5976 genes, and 204 miRNAs were differentially expressed (DE). KEGG analysis of DE genes indicated that ECM–receptor interaction and biosynthesis of amino acids were crucial for HF development. Notch, TGF-beta, and Wnt signaling pathways were also identified, which are conventional pathways associated with HF growth and development. Then, the ceRNA regulatory network was constructed, and the impact of lncRNA H19 was investigated in dermal papilla (DP) cells. The MTT, CCK-8, and EdU assays showed that the viability and proliferation of DP cells were promoted by H19, and mechanistic studies suggested that H19 performed its function through the chi-miR-214-3p/β-catenin axis. The present study created a resource for lncRNA, miRNA, and mRNA studies in cashmere morphogenesis. It could contribute to a better understanding of the molecular mechanism of ncRNAs involved in the regulation of HF growth and development.     

Roles of microRNAs and Long Non-Coding RNAs Encoded by Parasitic Helminths in Human Carcinogenesis

Infectious agents such as viruses, bacteria, and parasites can lead to cancer development. Infection with the helminthic parasite Schistosoma haematobium can cause cancer of the urinary bladder in humans, and infection with the parasites Clonorchis sinensis and Opisthorchis viverrini can promote cholangiocarcinoma. These three pathogens have been categorized as “group 1: carcinogenic to humans” by the International Agency for Research on Cancer (IARC). Additionally, the parasite Schistosoma japonicum has been associated with liver and colorectal cancer and classified as “group 2B: possibly carcinogenic to humans”. These parasites express regulatory non-coding RNAs as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), which modulate genic expression in different biological processes. In this review, we discuss the potential roles of miRNAS and lncRNAs encoded by helminthic parasites that are classified by the IARC as carcinogenic and possibly carcinogenic to humans. The miRNAs of these parasites may be involved in carcinogenesis by modulating the biological functions of the pathogen and the host and by altering microenvironments prone to tumor growth. miRNAs were identified in different host fluids. Additionally, some miRNAs showed direct antitumoral effects. Together, these miRNAs show potential for use in future therapeutic and diagnostic applications. LncRNAs have been less studied in these parasites, and their biological effects in the parasite–host interaction are largely unknown.     

The Relationship between the Aberrant Long Non-Coding RNA-Mediated Competitive Endogenous RNA Network and Alzheimer’s Disease Pathogenesis

Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by cognitive dysfunction. The role of long non-coding RNAs (lncRNAs) with the action of competitive endogenous RNA (ceRNA) in AD remains unclear. The present study aimed to identify significantly differentially expressed lncRNAs (SDELs) and establish lncRNA-associated ceRNA networks via RNA sequencing analysis and a quantitative real-time Polymerase Chain Reaction (qPCR) assay using transgenic mice with five familial AD mutations. A total of 53 SDELs in the cortex and 51 SDELs in the hippocampus were identified, including seven core SDELs common to both regions. The functions and pathways were then investigated through the potential target genes of SDELs via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, which indicate biological effects, action distributions, and pathological transductions associated with AD. Based on the ceRNA hypothesis, integrated ceRNA networks in the cortex and hippocampus of lncRNA-miRNA-mRNA were constructed. The core SDEL-mediated ceRNA relationship was established and the expression of these RNAs was verified by qPCR. The results identified lncRNA ENSMUST00000127786 and highlighted miRNAs and mRNAs as potential key mediators in AD. These findings provide AD-derived lncRNA-mediated ceRNA profiles, and further experimental evidence is needed to confirm these identified ceRNA regulatory relationships.     

Expression Profiles and Characteristics of Apple lncRNAs in Roots,Phloem, Leaves,Flowers, and Fruit

LncRNAs impart crucial effects on various biological processes, including biotic stress responses, abiotic stress responses, fertility and development. The apple tree is one of the four major fruit trees in the world. However, lncRNAs’s roles in different tissues of apple are unknown. We identified the lncRNAs in five tissues of apples including the roots, phloem, leaves, flowers, and fruit, and predicted the intricate regulatory networks. A total of 9440 lncRNAs were obtained. LncRNA target prediction revealed 10,628 potential lncRNA–messenger RNA (mRNA) pairs, 9410 pairs functioning in a cis-acting fashion, and 1218 acting in a trans-acting fashion. Functional enrichment analysis showed that the targets were significantly enriched in molecular functions related to photosynthesis-antenna proteins, single-organism metabolic process and glutathione metabolism. Additionally, a total of 88 lncRNAs have various functions related to microRNAs (miRNAs) as miRNA precursors. Interactions between lncRNAs and miRNAs were predicted, 1341 possible interrelations between 187 mdm-miRNAs and 174 lncRNAs (1.84%) were identified. MSTRG.121644.5, MSTRG.121644.8, MSTRG.2929.2, MSTRG.3953.2, MSTRG.63448.2, MSTRG.9870.2, and MSTRG.9870.3 could participate in the functions in roots as competing endogenous RNAs (ceRNAs). MSTRG.11457.2, MSTRG.138614.2, and MSTRG.60895.2 could adopt special functions in the fruit by working with miRNAs. A further analysis showed that different tissues formed special lncRNA–miRNA–mRNA networks. MSTRG.60895.2–mdm-miR393–MD17G1009000 may participate in the anthocyanin metabolism in the fruit. These findings provide a comprehensive view of potential functions for lncRNAs, corresponding target genes, and related lncRNA–miRNA–mRNA networks, which will increase our knowledge of the underlying development mechanism in apple.     

ncRNAs in Therapeutics: Challenges and Limitations in Nucleic Acid-Based Drug Delivery

Non-coding RNAs (ncRNAs) are emerging therapeutic tools but there are barriers to their translation to clinical practice. Key issues concern the specificity of the targets, the delivery of the molecules, and their stability, while avoiding “on-target” and “off-target” side effects. In this “ncRNA in therapeutics” issue, we collect several studies of the differential expression of ncRNAs in cardiovascular diseases, bone metabolism-related disorders, neurology, and oncology, and their potential to be used as biomarkers or therapeutic targets. Moreover, we review recent advances in the use of antisense ncRNAs in targeted therapies with a particular emphasis on their basic biological mechanisms, their translational potential, and future trends.     

Dynamic Nature of Noncoding RNA Regulation of Adaptive Immune Response

Immune response plays a fundamental role in protecting the organism from infections; however, dysregulation often occurs and can be detrimental for the organism, leading to a variety of immune-mediated diseases. Recently our understanding of the molecular and cellular networks regulating the immune response, and, in particular, adaptive immunity, has improved dramatically. For many years, much of the focus has been on the study of protein regulators; nevertheless, recent evidence points to a fundamental role for specific classes of noncoding RNAs (ncRNAs) in regulating development, activation and homeostasis of the immune system. Although microRNAs (miRNAs) are the most comprehensive and well-studied, a number of reports suggest the exciting possibility that long ncRNAs (lncRNAs) could mediate host response and immune function. Finally, evidence is also accumulating that suggests a role for miRNAs and other small ncRNAs in autocrine, paracrine and exocrine signaling events, thus highlighting an elaborate network of regulatory interactions mediated by different classes of ncRNAs during immune response. This review will explore the multifaceted roles of ncRNAs in the adaptive immune response. In particular, we will focus on the well-established role of miRNAs and on the emerging role of lncRNAs and circulating ncRNAs, which all make indispensable contributions to the understanding of the multilayered modulation of the adaptive immune response.     

The Emerging Role of Non-Coding RNAs in the Regulation of Virus Replication and Resultant Cellular Pathologies

Non-coding RNAs, particularly lncRNAs and miRNAs, have recently been shown to regulate different steps in viral infections and induction of immune responses against viruses. Expressions of several host and viral lncRNAs have been found to be altered during viral infection. These lncRNAs can exert antiviral function via inhibition of viral infection or stimulation of antiviral immune response. Some other lncRNAs can promote viral replication or suppress antiviral responses. The current review summarizes the interaction between ncRNAs and herpes simplex virus, cytomegalovirus, and Epstein–Barr infections. The data presented in this review helps identify viral-related regulators and proposes novel strategies for the prevention and treatment of viral infection.     

LncRNAs in Ovarian Cancer Progression,Metastasis, and Main Pathways: ceRNA and Alternative Mechanisms

Ovarian cancer (OvCa) develops asymptomatically until it reaches the advanced stages with metastasis, chemoresistance, and poor prognosis. Our review focuses on the analysis of regulatory long non-coding RNAs (lncRNAs) competing with protein-coding mRNAs for binding to miRNAs according to the model of competitive endogenous RNA (ceRNA) in OvCa. Analysis of publications showed that most lncRNAs acting as ceRNAs participate in OvCa progression: migration, invasion, epithelial-mesenchymal transition (EMT), and metastasis. More than 30 lncRNAs turned out to be predictors of survival and/or response to therapy in patients with OvCa. For a number of oncogenic (CCAT1, HOTAIR, NEAT1, and TUG1 among others) and some suppressive lncRNAs, several lncRNA/miRNA/mRNA axes were identified, which revealed various functions for each of them. Our review also considers examples of alternative mechanisms of actions for lncRNAs besides being ceRNAs, including binding directly to mRNA or protein, and some of them (DANCR, GAS5, MALAT1, and UCA1 among others) act by both mechanisms depending on the target protein. A systematic analysis based on the data from literature and Panther or KEGG (Kyoto Encyclopedia of Genes and Genomes) databases showed that a significant part of lncRNAs affects the key pathways involved in OvCa metastasis, EMT, and chemoresistance.     

Non-Coding RNAs: Prevention,Diagnosis, and Treatment in Myocardial Ischemia–Reperfusion Injury

Recent knowledge concerning the role of non-coding RNAs (ncRNAs) in myocardial ischemia/reperfusion (I/R) injury provides new insight into their possible roles as specific biomarkers for early diagnosis, prognosis, and treatment. MicroRNAs (miRNAs) have fewer than 200 nucleotides, while long ncRNAs (lncRNAs) have more than 200 nucleotides. The three types of ncRNAs (miRNAs, lncRNAs, and circRNAs) act as signaling molecules strongly involved in cardiovascular disorders (CVD). I/R injury of the heart is the main CVD correlated with acute myocardial infarction (AMI), cardiac surgery, and transplantation. The expression levels of many ncRNAs and miRNAs are highly modified in the plasma of MI patients, and thus they have the potential to diagnose and treat MI. Cardiomyocyte and endothelial cell death is the major trigger for myocardial ischemia–reperfusion syndrome (MIRS). The cardioprotective effect of inflammasome activation in MIRS and the therapeutics targeting the reparative response could prevent progressive post-infarction heart failure. Moreover, the pharmacological and genetic modulation of these ncRNAs has the therapeutic potential to improve clinical outcomes in AMI patients.