Class Of RNAs Research Articles

The pharmacogenomic and immune landscape of snoRNAs in human cancers

Small nucleolar RNAs (snoRNAs) are a class of non-coding RNAs primarily known for their role in the chemical modification of other RNAs. Recent studies suggested that snoRNAs may play a broader role in anti-cancer treatments such as targeted therapies and immunotherapies. Despite these insights, the comprehensive landscape of snoRNA associations with drug response and immunotherapy outcomes remains unexplored. In this study, we identified 79,448 and 75,185 associations between snoRNAs and drug response using data from VAEN and CancerRxTissue, respectively. Additionally, we discovered 29,199 associations between snoRNAs and immune checkpoint genes and 47,194 associations between snoRNAs and immune cell infiltrations. Sixteen snoRNAs were significantly correlated with immunotherapy objective response rate (ORR), and 92 snoRNAs showed significantly differential expression between cancers with high and low ORR. Furthermore, we identified 17 snoRNAs with significantly differential expression between cancer types with high and low immune-related adverse event (irAE) reporting odds ratio (ROR). Several snoRNAs, such as SNORD92, and SNORD83B, may represent promising biomarkers or therapeutic targets that needs further investigation. To facilitate further research, we developed a user-friendly portal, Pharmacogenomic and Immune Landscape of SnoRNA (PISNO, https://hanlaboratory.com/PISNO/), enabling researchers to visualize, browse, and download multi-dimensional data. This study highlights the potential of snoRNAs as biomarkers or therapeutic targets, paving the way for more effective and personalized anti-cancer treatments.

CircTMTC1 Mediates Nucleo-cytoplasmic Translocation of DDX3X to Regulate Osteogenic Differentiation of Human Ligamentum Flavum Cells.

This study was aimed to investigate the potential roles of circTMTC1 in the underlying pathophysiological mechanisms of ossification of the ligamentum flavum (OLF). OLF is the primary contributor to thoracic spinal stenosis, which may cause severe neurological symptoms. There is a lack of effective medical therapy for OLF available so far because the exact underlying mechanism of OLF has not been fully elucidated. CircRNAs are a special class of non-coding RNAs and have attracted a growing interest of research in various human diseases recently. Therefore, we explored the potential roles of circRNAs in the underlying pathophysiological mechanisms of OLF. We performed RNA-seq analysis to investigate the differentially expression profile of circRNAs in osteogenic differentiation of human LF cells, and identified a key circular RNA circTMTC1 functioned in OLF. Subsequently, we performed a series of experiments to investigate the exact molecular and cellular mechanisms in osteogenic differentiation of human ligamentum flavum cells. CircTMTC1 is significantly up-regulated during osteogenic differentiation of human LF cells. Mechanistically, we found that circTMTC1 could interact with the RNA binding protein DDX3X and enhance its nucleo-cytoplasmic translocation. An increased cytoplasmic level of DDX3X activated the NLRP3 inflammasome pathway and thus promoted osteogenic differentiation of human ligamentum flavum cells. Our findings suggested the circTMTC1-DDX3X-NLRP3 inflammasome signaling plays a pivotal role in osteogenic differentiation of human ligamentum flavum cells, which may provide novel diagnostic and therapeutic strategies for OLF.

Viroid-like colonists of human microbiomes.

Here, we describe "obelisks," a class of heritable RNA elements sharing several properties: (1) apparently circular RNA ∼1 kb genome assemblies, (2) predicted rod-like genome-wide secondary structures, and (3) open reading frames encoding a novel "Oblin" protein superfamily. A subset of obelisks includes a variant hammerhead self-cleaving ribozyme. Obelisks form their own phylogenetic group without detectable similarity to known biological agents. Surveying globally, we identified 29,959 distinct obelisks (clustered at 90% sequence identity) from diverse ecological niches. Obelisks are prevalent in human microbiomes, with detection in ∼7% (29/440) and ∼50% (17/32) of queried stool and oral metatranscriptomes, respectively. We establish Streptococcus sanguinis as a cellular host of a specific obelisk and find that this obelisk's maintenance is not essential for bacterial growth. Our observations identify obelisks as a class of diverse RNAs of yet-to-be-determined impact that have colonized and gone unnoticed in human and global microbiomes.

Cryo-EM Structure of raiA ncRNA From Clostridium Reveals a New RNA 3D Fold

Advancements in genome-wide sequence analysis have led to the discovery of numerous novel bacterial non-coding RNAs (ncRNAs). These ncRNAs have been categorized into various RNA families and classes based on their size, structure, function, and evolutionary relationships. One such ncRNA family, raiA, is notably abundant in the bacterial phyla Firmicutes and Actinobacteria and is remarkably well-conserved across many Gram-positive bacteria. In this study, we integrated cryo-electron microscopy single-particle analysis with computational modeling and biochemical techniques to elucidate the structural characteristics of raiA from Clostridium sp. CAG 138. Our findings reveal the globular 3D fold of raiA, providing valuable structural insights. This analysis paves the way for future investigations into the functional properties of raiA, potentially uncovering new regulatory mechanisms in bacterial ncRNAs.

Epididymis-specific RNase A family genes regulate fertility and small RNA processing

Sperm small RNAs are implicated in intergenerational transmission of paternal environmental effects. Small RNAs generated by cleavage of tRNAs, known as tRNA fragments (tRFs) or tRNA-derived RNAs (tDRs or tsRNAs), are an abundant class of RNAs in mature sperm and can be modulated by environmental conditions. The biogenesis of tRFs in the male reproductive tract remains poorly understood. Angiogenin, a member of the Ribonuclease A superfamily (RNase A), cleaves tRNAs to generate tRFs in response to cellular stress. Four paralogs of Angiogenin, namely Rnase9, Rnase10, Rnase11, and Rnase12, are specifically expressed in the epididymis -a long, convoluted tubule where sperm mature and acquire fertility and motility. Here, by generating mice deleted for all four genes (Rnase9-12-/-, termed "KO" for Knock Out), we report that these genes regulate fertility and small RNA levels. KO male mice are sterile; KO sperm fertilized oocytes in vitro but failed to efficiently fertilize oocytes in vivo due to an inability of sperm to pass through the utero-tubular junction. Intriguingly, there were decreased levels of fragments of tRNAs (tRFs) and rRNAs (rRNA-derived small RNAs or rsRNAs) in the KO epididymis and epididymal luminal fluid, although RNases 9-12 did not show ribonucleolytic activity in-vitro. Importantly, KO sperm showed a dramatic decrease in the levels of tRFs, demonstrating a role of epididymis-specific Rnase9-12 genes in regulating sperm small RNA composition. Together, our results reveal an unexpected role of four epididymis-specific non-canonical RNase A family genes in regulating fertility and small RNA processing.

Opportunities for Riboswitch Inhibition by Targeting Co-Transcriptional RNA Folding Events

Antibiotic resistance is a critical global health concern, causing millions of prolonged bacterial infections every year and straining our healthcare systems. Novel antibiotic strategies are essential to combating this health crisis and bacterial non-coding RNAs are promising targets for new antibiotics. In particular, a class of bacterial non-coding RNAs called riboswitches has attracted significant interest as antibiotic targets. Riboswitches reside in the 5′-untranslated region of an mRNA transcript and tune gene expression levels in cis by binding to a small-molecule ligand. Riboswitches often control expression of essential genes for bacterial survival, making riboswitch inhibitors an exciting prospect for new antibacterials. Synthetic ligand mimics have predominated the search for new riboswitch inhibitors, which are designed based on static structures of a riboswitch’s ligand-sensing aptamer domain or identified by screening a small-molecule library. However, many small-molecule inhibitors that bind an isolated riboswitch aptamer domain with high affinity in vitro lack potency in vivo. Importantly, riboswitches fold and respond to the ligand during active transcription in vivo. This co-transcriptional folding is often not considered during inhibitor design, and may explain the discrepancy between a low Kd in vitro and poor inhibition in vivo. In this review, we cover advances in riboswitch co-transcriptional folding and illustrate how intermediate structures can be targeted by antisense oligonucleotides—an exciting new strategy for riboswitch inhibitor design.

Human cells contain myriad excised linear intron RNAs with links to gene regulation and potential utility as biomarkers.

A previous study using Thermostable Group II Intron Reverse Transcriptase sequencing (TGIRT-seq) found human plasma contains short (≤300 nt) structured full-length excised linear intron (FLEXI) RNAs with potential to serve as blood-based biomarkers. Here, TGIRT-seq identified >9,000 different FLEXI RNAs in human cell lines, including relatively abundant FLEXIs with cell-type-specific expression patterns. Analysis of public CLIP-seq datasets identified 126 RNA-binding proteins (RBPs) that have binding sites within the region corresponding to the FLEXI or overlapping FLEXI splice sites in pre-mRNAs, including 53 RBPs with binding sites for ≥30 different FLEXIs. These included splicing factors, transcription factors, a chromatin remodeling protein, cellular growth regulators, and proteins with cytoplasmic functions. Analysis of ENCODE datasets identified subsets of these RBPs whose knockdown impacted FLEXI host gene mRNA levels or proximate alternative splicing, indicating functional interactions. Hierarchical clustering identified six subsets of RBPs whose FLEXI binding sites were co-enriched in six subsets of functionally related host genes: AGO1-4 and DICER, including but not limited to agotrons or mirtron pre-miRNAs; DKC1, NOLC1, SMNDC1, and AATF (Apoptosis Antagonizing Transcription Factor), including but not limited to snoRNA-encoding FLEXIs; two subsets of alternative splicing factors; and two subsets that included RBPs with cytoplasmic functions (e.g., LARP4, PABPC4, METAP2, and ZNF622) together with regulatory proteins. Cell fractionation experiments showed cytoplasmic enrichment of FLEXI RNAs with binding sites for RBPs with cytoplasmic functions. The subsets of host genes encoding FLEXIs with binding sites for different subsets of RBPs were co-enriched with non-FLEXI other short and long introns with binding sites for the same RBPs, suggesting overarching mechanisms for coordinately regulating expression of functionally related genes. Our findings identify FLEXIs as a previously unrecognized large class of cellular RNAs and provide a comprehensive roadmap for further analyzing their biological functions and the relationship of their RBPs to cellular regulatory mechanisms.

MicroRNA and Rare Human Diseases

Background: The role of microRNAs (miRNAs) in the pathogenesis of rare genetic disorders has been gradually discovered. MiRNAs, a class of small non-coding RNAs, regulate gene expression by silencing target messenger RNAs (mRNAs). Their biogenesis involves transcription into primary miRNA (pri-miRNA), processing by the DROSHA–DGCR8 (DiGeorge syndrome critical region 8) complex, exportation to the cytoplasm, and further processing by DICER to generate mature miRNAs. These mature miRNAs are incorporated into the RNA-induced silencing complex (RISC), where they modulate gene expression. Methods/Results: The dysregulation of miRNAs is implicated in various Mendelian disorders and familial diseases, including DICER1 syndrome, neurodevelopmental disorders (NDDs), and conditions linked to mutations in miRNA-binding sites. We summarized a few mechanisms how miRNA processing and regulation abnormalities lead to rare genetic disorders. Examples of such genetic diseases include hearing loss associated with MIR96 mutations, eye disorders linked to MIR184 mutations, and skeletal dysplasia involving MIR140 mutations. Conclusions: Understanding these molecular mechanisms is crucial, as miRNA dysregulation is a key factor in the pathogenesis of these conditions, offering significant potential for the diagnosis and potential therapeutic intervention.

RNA-Seq Analysis Revealed circRNAs Associated with Resveratrol-Induced Apoptosis of Porcine Ovarian Granulosa Cells.

Circular RNAs (circRNAs) are a class of circular non-coding RNAs that play essential roles in the intricate and dynamic networks governing cell growth, development, and apoptosis. Resveratrol (RSV), a non-flavonoid polyphenol, is known to participate in follicular development and ovulation. In our previous research, we established a model using porcine ovarian granulosa cells (POGCs) treated with resveratrol, which confirmed its regulatory effects on long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) within these cells. However, the influence of resveratrol on circRNA expression has not been thoroughly investigated. To explore how resveratrol affects circRNA levels in POGCs, we designed an experiment with three groups: a control group (CON, n = 3, 0 μM RSV), a low-dose RSV group (LOW, n = 3, 50 μM RSV), and a high-dose RSV group (HIGH, n = 3, 100 μM RSV) for circRNA sequencing. We identified a total of 10,045 candidate circRNAs from POGCs treated with different concentrations of resveratrol (0, 50, and 100 μM). Differential expression analysis indicated that 96 circRNAs were significantly altered in the LOW vs. CON group, while 109 circRNAs showed significant changes in the HIGH vs. CON group. These circRNAs were notably enriched in biological processes associated with cell metabolism, apoptosis, and oxidative stress. Functional enrichment analysis of the host genes revealed their involvement in critical signaling pathways, including mTOR, AMPK, and apoptosis pathways. Additionally, we identified potential miRNA sponge candidates among the differentially expressed circRNAs, particularly novel_circ_0012954 and novel_circ_0004762, which exhibited strong connectivity within miRNA-target networks. Our findings provide valuable insights into the regulatory mechanisms of circRNAs in the context of resveratrol-induced apoptosis in POGCs, highlighting their potential as innovative therapeutic targets in reproductive biology.

Evaluation of clinically significant miRNAs level by machine learning approaches utilizing total transcriptome data

Analysis of the mechanisms underlying the occurrence and progression of cancer represents a key objective in contemporary clinical bioinformatics and molecular biology. Utilizing omics data, particularly transcriptomes, enables a detailed characterization of expression patterns and post-transcriptional regulation across various RNA types relative to the entire transcriptome. Here, we assembled a dataset comprising transcriptomic data from approximately 16.000 patients encompassing over 160 types of cancer. We employed state-of-the-art gradient boosting algorithms to discern intricate correlations in the expression levels of four clinically significant microRNAs, specifically hsa-mir-21, hsa-let-7a-1, hsa-let-7b, and hsa-let-7i, with the expression levels of the remaining 60.660 unique RNAs. Our analysis revealed a dependence of the expression levels of the studied microRNAs on the concentrations of several small nucleolar RNAs and regulatory long non-coding RNAs. Notably, the roles of these RNAs in the development of specific cancer types had been previously established through experimental evidence. Subsequent evaluation of the created database will facilitate the identification of a broader spectrum of overarching dependencies related to changes in the expression levels of various RNA classes in diverse cancers. In future it will make possible discovery of unique alterations specific to certain types of malignant transformations.

Abstract B005: Characterizing the role of fibroadipogenic progenitors in pancreatic cancer cachexia: the role of miR-27a-3p

Abstract Introduction: Approximately 80% of patients with pancreatic cancer suffer from cachexia- a debilitating condition characterized by involuntary loss of muscle and fat. While muscle wasting has mostly been investigated from a whole tissue level, the impact of how different cell types contribute to muscle wasting remains elusive. The current study focuses on characterizing the role of muscle resident fibroadipogenic progenitors (FAPs) in pancreatic cancer cachexia. Dysregulation of FAPs produces sustained fibrogenic and/or adipogenic signals, which may lead to fibrofatty infiltration- a condition often observed in patients with cachexia. Using an experimental model of pancreatic cancer cachexia, we aim to understand (i) the overall contribution of FAPs to muscle wasting, (ii) the role of microRNAs (miRNAs- a class of small RNAs considered as global modulators of gene expression) in FAPs dysregulation and (iii) if modulating miRNAs in cancer improves muscle micro and macroenvironment. Methods: A male pancreatic cancer cell line was utilized to investigate the cachexia progression over time where day 14 (D14), 21 (D21), and day 26 (D26) were considered early, intermediate, and late time points, respectively. Mice were orthotopically implanted with 2 million pancreatic cancer cells (referred to as the KPC) and control mice received sham surgery (referred to as the control). Single nucleus RNA seq (snRNA seq) from quadriceps muscle, RNA seq, and miRNA profiling from sorted FAPs were performed. miR-27a-3p was knocked down in pancreatic cancer cells using a lentiviral system. Results: snRNA seq identified 13 clusters in quadriceps muscle including FAPs. Further, 4 subpopulations of FAPs with predominantly distinct transcriptional profiles were identified indicating that FAPs may be functionally heterogeneous. Further, muscle wasting genes such as Bmp4 and Osmr were present predominantly in FAPs suggesting that dysregulation of FAPs may contribute to muscle wasting. Time-resolved RNA seq analysis from sorted FAPs showed that alterations in adipogenesis (observed on day 14) preceded fibrosis (observed on d21), suggesting that dysregulation of FAPs is an early event in the muscle wasting trajectory, potentially contributing to fibrofatty infiltration. miR-27a-3p was chosen as a candidate molecule that was downregulated in FAPs and upregulated in the tumor when compared to controls. Inhibiting miR-27a-3p on FAPs increased adipogenesis and treatment with mimic reduced adipogenesis. Knocking down miR-27a in cancer prevented muscle wasting in vivo, and reduced FAPs dysregulation, suggesting that miR-27a-3p plays a dual role in tumor and muscle microenvironment. Conclusions: The study shows for the first time that dysregulation of FAPs significantly contributes to muscle wasting, potentially mediated through miR-27a-3p which when modulated in tumor reduces tumor progression and improves the muscle micro and macroenvironment. Citation Format: Ashok Narasimhan, Chun Wai Cheung, Nasim Kajabadi, Bruce Lin, Lin Wei Tung, Chihkai Chang, Fabio MV Rossi. Characterizing the role of fibroadipogenic progenitors in pancreatic cancer cachexia: the role of miR-27a-3p [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B005.

Advances in the study of the mechanism of action of miR‑22 in liver lesions (Review).

Globally, nearly 2 million deaths annually are attributed to the development of liver diseases, with liver cancer and cirrhosis being particularly prominent, which makes liver disease a significant global health concern. Cirrhosis is closely linked to the evolution of hepatitis, hepatic fibrosis and fatty liver. However, most liver diseases have an insidious onset, are challenging to treat and the prognosis and efficacy of current therapies are unsatisfactory, which can result in irreversible functional damage to the liver. Therefore, there is an urgent need to explore the molecular mechanisms underlying liver disease and identify new biomarkers and therapeutic targets. In previous years, microRNAs (miRs), a class of short non-coding RNAs comprising 17-25 nucleotides, have attracted attention for their roles in various types of liver diseases. Among them, miR-22 serves a unique role in mediating multiple pathway mechanisms and epigenetic modifications and can act both as an inhibitor of liver cancer and a metabolic blocker. Given its close association with the liver, several studies have reported that the differential expression of miR-22 regulates the metabolic process of liver cancer and is involved in the evolution of hepatic fibrosis and steatohepatitis, making it a potential target for early diagnosis and treatment. The present manuscript aimed to comprehensively review the key role of miR-22 in the evolution of liver diseases and offer valuable references and guidance for subsequent studies by identifying its specific mechanism of action and future development prospects.

A method for miRNA diffusion association prediction using machine learning decoding of multi-level heterogeneous graph Transformer encoded representations

MicroRNAs (miRNAs) are a key class of endogenous non-coding RNAs that play a pivotal role in regulating diseases. Accurately predicting the intricate relationships between miRNAs and diseases carries profound implications for disease diagnosis, treatment, and prevention. However, these prediction tasks are highly challenging due to the complexity of the underlying relationships. While numerous effective prediction models exist for validating these associations, they often encounter information distortion due to limitations in efficiently retaining information during the encoding-decoding process. Inspired by Multi-layer Heterogeneous Graph Transformer and Machine Learning XGboost classifier algorithm, this study introduces a novel computational approach based on multi-layer heterogeneous encoder—machine learning decoder structure for miRNA-disease association prediction (MHXGMDA). First, we employ the multi-view similarity matrices as the input coding for MHXGMDA. Subsequently, we utilize the multi-layer heterogeneous encoder to capture the embeddings of miRNAs and diseases, aiming to capture the maximum amount of relevant features. Finally, the information from all layers is concatenated to serve as input to the machine learning classifier, ensuring maximal preservation of encoding details. We conducted a comprehensive comparison of seven different classifier models and ultimately selected the XGBoost algorithm as the decoder. This algorithm leverages miRNA embedding features and disease embedding features to decode and predict the association scores between miRNAs and diseases. We applied MHXGMDA to predict human miRNA-disease associations on two benchmark datasets. Experimental findings demonstrate that our approach surpasses several leading methods in terms of both the area under the receiver operating characteristic curve and the area under the precision-recall curve.

MRDPDA: A multi-Laplacian regularized deepFM model for predicting piRNA-disease associations.

PIWI-interacting RNAs (piRNAs) are a typical class of small non-coding RNAs, which are essential for gene regulation, genome stability and so on. Accumulating studies have revealed that piRNAs have significant potential as biomarkers and therapeutic targets for a variety of diseases. However current computational methods face the challenge in effectively capturing piRNA-disease associations (PDAs) from limited data. In this study, we propose a novel method, MRDPDA, for predicting PDAs based on limited data from multiple sources. Specifically, MRDPDA integrates a deep factorization machine (deepFM) model with regularizations derived from multiple yet limited datasets, utilizing separate Laplacians instead of a simple average similarity network. Moreover, a unified objective function to combine embedding loss about similarities is proposed to ensure that the embedding is suitable for the prediction task. In addition, a balanced benchmark dataset based on piRPheno is constructed and a deep autoencoder is applied for creating reliable negative set from the unlabeled dataset. Compared with three latest methods, MRDPDA achieves the best performance on the pirpheno dataset in terms of the five-fold cross validation test and independent test set, and case studies further demonstrate the effectiveness of MRDPDA.

FlaHMM: unistrand flamenco-like piRNA cluster prediction in Drosophila species using hidden Markov models.

PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs that are essential for transposon control in animal gonads. In Drosophila ovarian somatic cells, piRNAs are transcribed from large genomic regions called piRNA clusters, which are enriched for transposon fragments and act as a memory of past invasions. Despite being widely present across Drosophila species, somatic piRNA clusters are difficult to identify and study due to their lack of sequence conservation and limited synteny. Current identification methods rely on either extensive manual curation or availability of high-throughput small RNA sequencing data, limiting large-scale comparative studies. We now present FlaHMM, a hidden Markov model developed to automate genomic annotation of flamenco-like unistrand piRNA clusters in Drosophila species, requiring only a genome assembly and transposon annotations. FlaHMM uses transposable element content across 5- or 10-kb bins, which can be calculated from genome sequence alone, and is thus able to detect candidate piRNA clusters without the need to obtain flies and experimentally perform small RNA sequencing. We show that FlaHMM performs on par with piRNA-guided or manual methods, and thus provides a scalable and efficient approach to piRNA cluster annotation in new genome assemblies. FlaHMM is freely available at https://github.com/Hannon-lab/FlaHMM under an MIT licence.

Serum tsncRNAs reveals novel potential therapeutic targets of Salvianolic Acid B on atherosclerosis

BackgroundSalvianolic Acid B (SalB) has been proven to delay the progression of atherosclerosis. The therapeutic mechanisms of this compound are unclear. A novel class of short non-coding RNAs, pre-transfer RNA and mature transfer RNA (tsncRNAs) may regulate gene expression. TsncRNAs-sequencing revealed novel therapeutic targets for SalB. This is the first study focusing on tsncRNAs to treat atherosclerosis using SalB. PurposeTo explore the potential mechanism of SalB treating atherosclerosis through tsncRNAs. MethodsFive groups of mice were created at random: control group (CON), atherosclerosis model group (MOD), SalB with high dose-treated group (SABH), SalB with low dose-treated group (SABL), and Simvastatin-treated group (ST). Aortic sinus plaque, body weight and inflammatory cytokines were evaluated. The Illumina NextSeq equipment was used to do expression profiling of tsncRNAs from serum. The targets of tsncRNAs were then predicted using tRNAscan and TargetScan. The KEGG pathway and GO analysis were utilized to forecast the bioinformatics analysis. Potential tsncRNAs and associated mRNAs were validated using quantitative real-time PCR. ResultstRF-Glu-CTC-014 and tRF-Gly-GCC-074 were markedly increased by SalB with high dose treatment and validated with quantitative real-time PCR. Two mRNAs SRF and Arrb related to tRF-Glu-CTC-014 changed consistently. GO analysis revealed that the altered target genes of the selected tsncRNAs were most enriched in protein binding and cellular process. Moreover, KEGG pathway analysis demonstrated that altered target genes of tsncRNAs were most enriched in MAPK signaling pathway. ConclusionSalB can promote the expression of tRF-Glu-CTC-014 to treat atherosclerosis.

O69 THE REGULATORY ROLE OF CIRCULAR RNAS IN RESPONSE TO RAAS INHIBITORS

Circular RNAs (circRNAs) are a class of non-coding RNA that may play an important role in disease progression and diagnosis. This study aimed to investigate the role of renal circRNAs in hypertension and to identify circRNAs pathways explaining chronic reset in blood pressure. Two groups of young spontaneously hypertensive rats (SHR) were used: rats treated with or without losartan (RAAS inhibitor, n = 18 in each group). Through established circRNA identification and quantification tools, we identified five significant circular RNA candidates (P < 0.05), each aligning with differentially expressed and biologically significant miRNA. Furthermore, these candidate circRNAs aligned with expression pathways found in both treatment and control groups. In conclusion, this study identified several circRNAs which may play an important role in blood pressure regulation. It may advance our understanding of circRNAs in mediating losartan-induced blood pressure reduction. Future studies on validation, expression networking and methylome analysis may shed light on these circRNAs’ significance and identify potential therapeutic biomarkers.

Dysregulated MicroRNAs in Chronic Lymphocytic Leukemia.

MiRNAs are a class of non-coding RNAs acting as gene expression regulators by modulating the lifespan of messenger RNA. Commonly referred to as the most frequent leukemia in the Western world, chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy characterized by clonal expansion of CD19, CD23, and CD5-positive mature B-cells. While this pathology is regarded as less aggressive and has a variety of treatment options, the cause of its clinical heterogeneity is not yet understood. Moreover, the prognostic markers and treatment recommendations based on predictive markers are limited. This review aims to investigate some miRNAs that are dysregulated and possibly involved in CLL pathogenesis as a starting point for the proposal of new prognostic and predictive markers and, as more agents targeting miRNA expression become available, their potential role as therapeutic targets.

The small noncoding RNA Vaultrc5 is dispensable to mouse development.

Vault RNAs (vtRNAs) are evolutionarily conserved small noncoding RNAs transcribed by RNA polymerase III. Vault RNAs were initially described as components of the vault particle, but have since been assigned multiple vault-independent functions, including regulation of PKR activity, apoptosis, autophagy, lysosome biogenesis, and viral particle trafficking. The full-length transcript has also been described as a noncanonical source of miRNAs, which are processed in a DICER-dependent manner. As central molecules in vault-dependent and independent processes, vtRNAs have been attributed numerous biological roles, including regulation of cell proliferation and survival, response to viral infections, drug resistance, and animal development. Yet, their impact to mammalian physiology remains largely unexplored. To study vault RNAs in vivo, we generated a mouse line with a conditional Vaultrc5 loss-of-function allele. Because Vaultrc5 is the sole murine vtRNA, this allele enables the characterization of the physiological requirements of this conserved class of small regulatory RNAs in mammals. Using this strain, we show that mice constitutively null for Vaultrc5 are viable and histologically normal but have a slight reduction in platelet counts, pointing to a potential role for vtRNAs in hematopoiesis. This work paves the way for further in vivo characterizations of this abundant but mysterious RNA molecule. Specifically, it enables the study of the biological consequences of constitutive or lineage-specific Vaultrc5 deletion and of the physiological requirements for an intact Vaultrc5 during normal hematopoiesis or in response to cellular stresses such as oncogene expression, viral infection, or drug treatment.

Epididymis-specific RNase A family genes regulate fertility and small RNA processing.

Sperm small RNAs are implicated in intergenerational transmission of paternal environmental effects. Small RNAs generated by cleavage of tRNAs, known as tRNA fragments (tRFs), are an abundant class of RNAs in mature sperm, and can be modulated by environmental conditions. The ribonuclease(s) responsible for the biogenesis of tRFs in the male reproductive tract remains unknown. Angiogenin, a member of the Ribonuclease A superfamily (RNase A), cleaves tRNAs to generate tRFs in response to cellular stress. Four paralogs of Angiogenin, namely Rnase9, Rnase10, Rnase11, and Rnase12, are specifically expressed in the epididymis-a long, convoluted tubule where sperm mature and acquire fertility and motility. The biological functions of these genes remain largely unknown. Here, by generating mice deleted for all four genes (Rnase9-12-/-, termed "KO" for Knock Out), we report that these genes regulate fertility and RNA processing. KO mice showed complete male sterility. KO sperm fertilized oocytes in vitro but failed to efficiently fertilize oocytes in vivo, likely due to an inability of sperm to pass through the utero-tubular junction. Intriguingly, there were decreased levels of fragments of tRNAs (tRFs) and rRNAs (rRNA-derived small RNAs or rsRNAs) in the KO epididymis and epididymal luminal fluid, implying that Rnase9-12 regulate the biogenesis and/or stability of tRFs and rsRNAs. Importantly, KO sperm showed a dramatic decrease in the levels of tRFs, demonstrating a role of Rnase9-12 in regulating sperm RNA composition. Together, our results reveal an unexpected role of four epididymis-specific non-canonical RNase A family genes in fertility and RNA processing.