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Background and Aims: Severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) preferentially infects the respiratory tract; however, several studies have implicated a multi‐organ involvement. Hepatic dysfunctions caused by SARS‐CoV‐2 infection have been increasingly recognized and described to correlate with disease severity. To elucidate molecular factors that could contribute towards hepatic infection, we concentrated on microRNAs (miRNAs), a class of small non‐coding RNAs that modulate various cellular processes and which are reported to be differentially regulated during liver injury. We aimed to study the infection of primary human hepatocytes (PHH) with SARS‐CoV‐2 and to evaluate the potential of miRNAs for modulating viral infection. Methods: We analysed liver autopsies from a coronavirus disease 19 (COVID‐19)‐positive cohort for the presence of viral RNA using Nanopore sequencing. PHH were used for the infection with SARS‐CoV‐2. The candidate miRNAs targeting angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) were identified using in silico approaches. To discover the potential regulatory mechanism, transfection experiments, qRT‐PCRs, western blots and luciferase reporter assays were performed. Results: We could detect SARS‐CoV‐2 RNA in COVID‐19‐positive liver autopsies. We show that PHH express ACE2 and TMPRSS2 and can be readily infected with SARS‐CoV‐2, resulting in robust replication. Transfection of selected miRNA mimics reduced SARS‐CoV‐2 receptor expression and SARS‐CoV‐2 burden in PHH. In silico and biochemical analyses supported a potential direct binding of miR‐141‐3p to the SARS‐CoV‐2 genome. Conclusion: We confirm that PHH are susceptible to SARS‐CoV‐2 infection and demonstrate selected miRNAs targeting SARS‐CoV‐2 entry factors and/or the viral genome reduce viral loads. These data provide novel insights into hepatic susceptibility to SARS‐CoV‐2 and associated dysfunctions in COVID‐19. [ABSTRACT FROM AUTHOR]

Background: Personalized medicine represents a novel and integrative approach that focuses on an individual's genetics and epigenetics, precision medicine, lifestyle and exposures as key players of health status and disease phenotypes. Methods: In this narrative review, we aim to carefully discuss the current knowledge on gender disparities in cardiometabolic diseases, and we consider the sex‐ specific expression of miRNAs and their role as promising tool in precision medicine. Results: Personalised medicine overcomes the restricted care of patient based on a binomial sex approach, by enriching itself with a holistic and dynamic gender integration. Recognized as a major worldwide health emergency, cardiometabolic disorders continue to rise, impacting on health systems and requiring more effective and targeted strategies. Several sex and gender drivers might affect the onset and progression of cardiometabolic disorders in males and females at multiple levels. In this respect, distinct contribution of genetic and epigenetic mechanisms, molecular and physiological pathways, sex hormones, visceral fat and subcutaneous fat and lifestyle lead to differences in disease burden and outcomes in males and females. Conclusions: Sex and gender play a pivotal role in precision medicine because the influence the physiology of each individual and the way they interact with environment from intrauterine life. [ABSTRACT FROM AUTHOR]

The hypothalamic–pituitary axis is central to the functioning of the neuroendocrine system and essential for regulating physiological and behavioral homeostasis and coordinating fundamental body functions. The expanding line of evidence shows the indispensable role of the microRNA pathway in regulating the gene expression profile in the developing and adult hypothalamus and pituitary gland. Experiments provoking a depletion of miRNA maturation in the context of the hypothalamic–pituitary axis brought into focus a prominent involvement of miRNAs in neuroendocrine functions. There are also a few individual miRNAs and miRNA families that have been studied in depth revealing their crucial role in mediating the regulation of fundamental processes such as temporal precision of puberty timing, hormone production, fertility and reproduction capacity, and energy balance. Among these miRNAs, miR‐7 was shown to be hypothalamus‐enriched and the top one highly expressed in the pituitary gland, where it has a profound impact on gene expression regulation. Here, we review miRNA profiles, knockout phenotypes, and miRNA interaction (targets) in the hypothalamic–pituitary axis that advance our understanding of the roles of miRNAs in mammalian neurosecretion and related physiology. [ABSTRACT FROM AUTHOR]

Life expectancy in cancer patients has been extended in recent years, thanks to major breakthroughs in therapeutic developments. However, this also unmasked an increased incidence of cardiovascular diseases in cancer survivors, which is in part attributable to cancer therapy‐related cardiovascular toxicity. Non‐coding RNAs (ncRNAs) have received much appreciation due to their impact on gene expression. NcRNAs, which include microRNAs, long ncRNAs and circular RNAs, are non‐protein‐coding transcripts that are involved in the regulation of various biological processes, hence shaping cell identity and behaviour. They have also been implicated in disease development, including cardiovascular diseases, cancer and, more recently, cancer therapy‐associated cardiotoxicity. This review outlines key features of cancer therapy‐associated cardiotoxicity, what is known about the roles of ncRNAs in these processes and how ncRNAs could be exploited as therapeutic targets for cardioprotection. [ABSTRACT FROM AUTHOR]

Summary: Despite the substantial progress in multiple myeloma (MM) therapy nowadays, treatment resistance and disease relapse remain major clinical hindrances. Herein, we have investigated tRNA‐derived fragment (tRF) profiles in MM and precursor stages (smoldering MM/sMM; monoclonal gammopathy of undetermined significance/MGUS), aiming to unveil potential MM‐related tRFs in ameliorating MM prognosis and risk stratification. Small RNA‐seq was performed to profile tRFs in bone marrow CD138+ plasma cells, revealing the significant deregulation of the mitochondrial internal tRFHisGTG (mt‐i‐tRFHisGTG) in MM versus sMM/MGUS. The screening cohort of the study consisted of 147 MM patients, and mt‐i‐tRFHisGTG levels were quantified by RT‐qPCR. Disease progression was assessed as clinical end‐point for survival analysis, while internal validation was performed by bootstrap and decision curve analyses. Screening cohort analysis highlighted the potent association of reduced mt‐i‐tRFHisGTG levels with patients' bone disease (p = 0.010), osteolysis (p = 0.023) and with significantly higher risk for short‐term disease progression following first‐line chemotherapy, independently of patients' clinical data (HR = 1.954; p = 0.036). Additionally, mt‐i‐tRFHisGTG‐fitted multivariate models led to superior risk stratification of MM patients' treatment outcome and prognosis compared to disease‐established markers. Notably, our study highlighted mt‐i‐tRFHisGTG loss as a powerful independent indicator of post‐treatment progression of MM patients, leading to superior risk stratification of patients' treatment outcome. [ABSTRACT FROM AUTHOR]

Aim: There has been an increased focus on regulating cell function with Rho family GTPases, including proliferation, migration/invasion, polarity, and adhesion. Due to the challenges involved in targeting Rho family GTPases directly, it may be more effective to target their regulators, such as Rho GTPase‐activating protein 1 (ARHGAP1). This present research was performed to define the clinical significance of ARHGAP1 expression, as well as its regulatory mechanisms in hepatocellular carcinoma. Methods: ARHGAP1 and miR‐101‐3p expression of liver cancer patients, and their relevance with clinicopathological characteristics and prognosis were analyzed by the Cancer Genome Atlas sequencing data, and verified using samples of hepatocellular carcinoma patients. The interactions between miR‐101‐3p and ARHGAP1 or circPIP5K1A were validated by bioinformatic analyses, as well as confirmed by quantitative reverse transcription polymerase chain reaction, western blotting, and dual‐luciferase reporter analysis. Plate clonality assays, cell adhesion and migration experiments, and proliferation experiments were used for assessing the participation of the circPIP5K1A/miR‐101‐3p/ARHGAP1 pathway in cell proliferation and motility. Results: Elevated ARHGAP1 and reduced miR‐101‐3p expression are related to poorer survival. MiR‐101‐3p targets ARHGAP1 to suppress hepatocellular carcinoma cell colony formation and invasion, whereas miR‐101‐3p inhibitor reverses liver cancer proliferation and metastasis suppression caused by ARHGAP1 knockdown. In addition, circPIP5K1A, which is mainly distributed in the cytosol, showed carcinogenic effects by sponging miR‐101‐3p, thus regulating ARHGAP1 expression. Conclusions: ARHGAP1 serves as an oncogenic gene in liver cancer, and the expression thereof is regulated by circPIP5K1A through sponging miR‐101‐3p. [ABSTRACT FROM AUTHOR]

Background: The primary reason for tumor‐related deaths worldwide is lung adenocarcinoma (LUAD). The oncogene IQ motif‐containing GTPase activating protein 3 (IQGAP3) is crucial for contributing to tumor initiation and progression. However, the precise function and molecular mechanism of IQGAP3 in LUAD remain unknown. The present study aimed to investigate the expression, prognosis, mechanism and tumor immunity associated with IQGAP3 in LUAD. Methods: The relationship between IQGAP3 and the poor prognosis of LUAD was analyzed using The Cancer Genome Atlas (TCGA) database. This analysis was further validated on lung cancer tissues and cell lines. The function of IQGAP3 was investigated by silencing it in LUAD cell lines. To predict microRNA (miRNA) and long non‐coding RNA associated with IQGAP3, the starBase database was utilized, and the predictions were verified by enhancing the function of miRNA. Finally, the relationship between IQGAP3 and tumor immunity was evaluated using Spearman's correlation analysis. Results: TCGA database revealed that higher levels of IQGAP3 were associated with advanced tumor stage, N stage and poor prognosis in LUAD patients. To confirm that, we conducted experiments on lung cancer tissues and cell lines and found that silencing IQGAP3 significantly inhibited tumor cell proliferation and migration. The expression of IQGAP3 showed a negative correlation with has‐miR‐101‐3p and has‐miR‐135a‐5p, whereas it showed a positive correlation with GSEC, AC005034.3 and TYMSOS. Furthermore, the introduction of miRNA‐mimics into lung cancer cell resulted in a significant inhibition of cancer cell growth and migration. Following that, the level of IQGAP3 showed a positive correlation with the infiltration of immune cells in tumors. Conclusions: These results reveal that IQGAP3 significantly promotes LUAD progression and could serve as a prognostic biomarker for LUAD. Furthermore, IQGAP3 is most likely regulated by the GSEC/TYMSOS‐hsa‐miR‐101‐3p axis and the AC005034.3‐hsa‐miR‐135a‐5p axis in LUAD. [ABSTRACT FROM AUTHOR]

Background: COVID‐19 is a novel infectious disease for which no specific treatment exists. It is likely that a combination of genetic and non‐genetic factors predispose to it. Expression levels of genes that are involved in the interaction with SARS‐CoV‐2 or the host response are thought to play a role in disease susceptibility and severity. It is crucial to explore biomarkers for disease severity and outcome. Herein, we studied the expression levels and effects of long non‐coding metastasis‐associated lung adenocarcinoma transcript 1 (lnc‐MALAT1) and long non‐coding maternally expressed gene 3 (lnc‐MEG3) in COVID‐19 patients. The study enrolled 35 hospitalized and 35 non‐hospitalized COVID‐19 patients, and 35 healthy controls. A chest computed tomography (CT) scan, complete blood count (CBC), ferritin, C‐reactive protein (CRP), D‐dimer and analysis of lnc‐MALAT1 and lnc‐MEG3 expression were done. Results: There was a significant relation between ferritin, CRP, D‐dimer levels, oxygen saturation, CT‐CORADS score and disease severity. Lnc‐MALAT1 was significantly higher but lnc‐MEG3 was significantly lower in patients vs. controls, and in hospitalized vs. non‐hospitalized patients. Elevated MALAT1 and reduced MEG3 levels were significantly associated with more elevated ferritin, CRP, D‐dimer levels, lower oxygen saturation, higher CT‐CORADS score and poor survival. Moreover, MALAT1 and MEG3 levels displayed higher sensitivity and specificity as predictors of COVID‐19 severity compared with other prognostic biochemical markers such as ferritin, CRP, and D‐dimer. Conclusions: MALAT1 levels are higher, whereas MEG3 levels are lower in COVID‐19 patients. Both are linked to disease severity and mortality and could emerge as predictive biomarkers for COVID‐19 severity and therapeutic targets. [ABSTRACT FROM AUTHOR]

Transcription of actively expressed genes is dampened for kilobases around DNA lesions via chromatin modifications. This is believed to favour repair and prevent genome instability. Nonetheless, mounting evidence suggests that transcription may be induced by DNA breakage, resulting in the local de novo synthesis of non‐coding RNAs (ncRNAs). Such transcripts have been proposed to play important functions in both DNA damage signalling and repair. Here, we review the recently identified mechanistic details of transcriptional silencing at damaged chromatin, highlighting how post‐translational histone modifications can also be modulated by the local synthesis of DNA damage‐induced ncRNAs. Finally, we envision that these entangled transcriptional events at DNA breakages can be targeted to modulate DNA repair, with potential implications for locus‐specific therapeutic strategies. [ABSTRACT FROM AUTHOR]

LncRNAs and miRNAs are the two most important non‐coding RNAs, which have been identified to be associated with cancer progression or prevention. The dysregulation of lncRNAs conducts tumorigenesis and metastasis in different ways. One of the mechanisms is that lncRNAs interact with miRNAs to regulate distinct cellular and genomic processes and cancer progression. LncRNA SNHG7 as an oncogene sponges miRNAs and develops lncRNA‐miRNA‐mRNA axes, leading to the regulation of several signaling pathways such as Wnt/β‐Catenin, PI3K/AKT/mTOR, SIRT1, and Snail‐EMT. Therefore, in this article, after a brief overview of lncRNA SNHG7‐miRNA‐mRNA axes' contribution to cancer development, we will discuss the role of lncRNA SNHG7 in the genes expression and signaling pathways related to cancers development via acting as a ceRNA. [ABSTRACT FROM AUTHOR]

Background: Colitis‐associated cancer (CAC) is one of the most severe complications of inflammatory bowel disease (IBD), which has caused a worse survival rate in IBD patients. Although the exact aetiology and pathogenesis of CAC are not completely elucidated, evidence indicates that non‐coding RNAs are closely involved and play a key role. Methods: This review aims to summarise the major findings of non‐coding RNAs in the development of CAC and present the potential mechanistic links between non‐coding RNAs and CAC pathogenesis. The results show that non‐coding RNAs can hinder DNA mismatch repair proteins and obstruct chromosome passenger complexes to increase microsatellite instability and accumulate chromosomal instability, respectively. The data also suggest that DNA promoter methylation or RNA methylation modifications of non‐coding RNA are the main mechanisms to regulate oncogene or tumour suppressor expression during the CAC progression. Other factors, including gut microbiota perturbations, immune dysregulation and barrier dysfunction, are also regulated and influenced by non‐coding RNAs. Besides, non‐coding RNAs as molecular managers are associated with multiple critical signalling pathways governing the initiation, progression and metastasis of CAC, including the janus kinase/signal transducer and activator of transcription (JAK/STAT), nuclear factor‐kappa B (NF‐κB), extracellular signal‐regulated kinase (ERK), Toll‐like receptor 4 (TLR4), Wnt/β‐catenin and phosphatidylinositol 3‐Kinase/Protein Kinase B (PI3K/AKT) pathways. In addition, non‐coding RNAs can be detected in colon tissues or blood, and their aberrant expressions and diagnostic and prognostic roles are also discussed and confirmed in CAC patients. Conclusions: It is believed that a deepening understanding of non‐coding RNAs in CAC pathogenesis may prevent the progression to carcinogenesis, and will offer new effective therapies for CAC patients. [ABSTRACT FROM AUTHOR]

While heredity is predominantly controlled by what deoxyribonucleic acid (DNA) sequences are passed from parents to their offspring, a small but growing number of traits have been shown to be regulated in part by the non‐genetic inheritance of information. Transgenerational epigenetic inheritance is defined as heritable information passed from parents to their offspring without changing the DNA sequence. Work of the past seven decades has transitioned what was previously viewed as rare phenomenology, into well‐established paradigms by which numerous traits can be modulated. For the most part, studies in model organisms have correlated transgenerational epigenetic inheritance phenotypes with changes in epigenetic modifications. The next steps for this field will entail transitioning from correlative studies to causal ones. Here, we delineate the major molecules that have been implicated in transgenerational epigenetic inheritance in both mammalian and non‐mammalian models, speculate on additional molecules that could be involved, and highlight some of the tools which might help transition this field from correlation to causation. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) is a mosquito‐borne flavivirus that causes frequent outbreaks in tropical countries. Due to the four different serotypes and ever‐mutating RNA genome, it is challenging to develop efficient therapeutics. Early diagnosis is crucial to prevent the severe form of dengue, leading to mortality. In the past decade, rapid advancement in the high throughput sequencing technologies has shed light on the crucial regulating role of non‐coding RNAs (ncRNAs), also known as the "dark matter" of the genome, in various pathological processes. In addition to the human host ncRNAs like microRNAs and circular RNAs, DENV also produces ncRNAs such as subgenomic flaviviral RNAs that can modulate the virus life cycle and regulate disease outcomes. This review outlines the advances in understanding the interplay between the human host and DENV ncRNAs, their regulation of the innate immune system of the host, and the prospects of the ncRNAs in clinical applications such as dengue diagnosis and promising therapeutics. [ABSTRACT FROM AUTHOR]

SUMMARY: Ripening is the last, irreversible developmental stage during which fruit become palatable, thus promoting seed dispersal by frugivory. In Alisa Craig fruit, mRNAs with increasing m5C levels, such as STPK and WRKY 40, were identified as being involved in response to biotic and abiotic stresses. Furthermore, two mRNAs involved in cell wall metabolism, PG and EXP‐B1, also presented increased m5C levels. In the Nr mutant, several m5C‐modified mRNAs involved in fruit ripening, including those encoding WRKY and MADS‐box proteins, were found. Targets of long non‐coding RNAs and circular RNAs with different m5C sites were also found; these targets included 2‐alkenal reductase, soluble starch synthase 1, WRKY, MADS‐box, and F‐box/ketch‐repeat protein SKIP11. A combined analysis of changes in 5mC methylation and mRNA revealed many differentially expressed genes with differentially methylated regions encoding transcription factors and key enzymes related to ethylene biosynthesis and signal transduction; these included ERF084, EIN3, AP2/ERF, ACO5, ACS7, EIN3/4, EBF1, MADS‐box, AP2/ERF, and ETR1. Taken together, our findings contribute to the global understanding of the mechanisms underlying fruit ripening, thereby providing new information for both fruit and post‐harvest behavior. Significance Statement: This is the first study on the regulation of RNA (m5C) methylation and non‐coding RNA (m5C) methylation on tomato fruit ripening in the world, which will establish a great foundation for tomato breeding and fresh fruit ripening regulation research. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is known as a risk factor for pancreatic cancer (PC). Various genetic and environmental factors cause both these global chronic diseases. The mechanisms that define their relationships are complex and poorly understood. Recent studies have implicated that metabolic abnormalities, including hyperglycemia and hyperinsulinemia, could lead to cell damage responses, cell transformation, and increased cancer risk. Hence, these kinds of abnormalities following molecular events could be essential to develop our understanding of this complicated link. Among different molecular events, focusing on shared signaling pathways including metabolic (PI3K/Akt/mTOR) and mitogenic (MAPK) pathways in addition to regulatory mechanisms of gene expression such as those involved in non‐coding RNAs (miRNAs, circRNAs, and lncRNAs) could be considered as powerful tools to describe this association. A better understanding of the molecular mechanisms involved in the development of type 2 diabetes and pancreatic cancer would help us to find a new research area for developing therapeutic and preventive strategies. For this purpose, in this review, we focused on the shared molecular events resulting in type 2 diabetes and pancreatic cancer. First, a comprehensive literature review was performed to determine similar molecular pathways and non‐coding RNAs; then, the final results were discussed in more detail. [ABSTRACT FROM AUTHOR]

The role of miRNAs and its regulatory mechanism in myopia are indeterminate. Our study aimed to investigate potential myopia‐associated non‐coding RNAs and related molecules by performing a comprehensive bioinformatic analysis of miRNA expression profile of mice with form‐deprivation myopia (FDM). Differentially expressed miRNAs in two raw microarray data sets (GSE58124 and GSE84220) from Gene Expression Omnibus (GEO) database were comprehensively analysed using GEO2R. Target genes were predicted using miRDB and enriched with Metascape online tool. Protein‐protein interaction (PPI) networks were constructed utilizing STRING and Cytoscape. Significant differentially expressed miRNAs were validated by real‐time polymerase chain reaction (qRT‐PCR) using RNA extracted from monocular FDM ocular tissues. As result, we identified three upregulated miRNAs (mmu‐miR‐1936, mmu‐miR‐338‐5p, and mmu‐miR‐673‐3p) significantly associated with myopia in the two microarray data sets (p < 0.05 and |Log (Fold Change) |>1). GO functional analysis suggested these three miRNAs were targeted in genes mostly enriched in morphogenesis and developmental growth of retinal tissues. Enrichment analysis revealed top eight transcription factors, including PAX6 and Smad3, related to myopia. Ten hub genes, including Rbx1, Fbxl3, Fbxo27, Fbxl7, Fbxo4, Cul3, Cul2, Klhl5, Fbxl16 and Klhl42, associated with ubiquitin conjugation were identified. qRT‐PCR confirmed the increased expression of mmu‐miR‐1936 and mmu‐miR‐338‐5p (p < 0.05), but no statistical difference was observed in mmu‐miR‐673‐3p expression in myopic retinas. Our findings indicated mmu‐miR‐1936, mmu‐miR‐338‐5p and mmu‐miR‐673‐3p upregulation may be associated with myopia development via post‐transcriptional gene regulation, and identified potential molecules that could be further explored in future studies of the mechanism in myopia. [ABSTRACT FROM AUTHOR]

From the initial sensing of viral nucleotides by pattern recognition receptors, through the induction of type I and III interferons (IFN), upregulation of antiviral effector proteins, and resolution of the inflammatory response, each step of innate immune signaling is under tight control. Though innate immunity is often associated with broad regulation at the level of gene transcription, RNA‐centric post‐transcriptional processes have emerged as critical mechanisms for ensuring a proper antiviral response. Here, we explore the diverse RNA regulatory mechanisms that modulate the innate antiviral immune response, with a focus on RNA sensing by RIG‐I‐like receptors (RLR), interferon (IFN) and IFN signaling pathways, viral pathogenesis, and host genetic variation that contributes to these processes. We address the post‐transcriptional interactions with RNA‐binding proteins, non‐coding RNAs, transcript elements, and modifications that control mRNA stability, as well as alternative splicing events that modulate the innate immune antiviral response. [ABSTRACT FROM AUTHOR]

Ample proof showed that non‐coding RNAs (ncRNAs) play a crucial role in proliferation and differentiation of osteoblasts and bone marrow stromal cells (BMSCs). Varied forms of biophysical stimuli like mechanical strain, fluid shear stress (FSS), microgravity and vibration are verified to regulate ncRNAs expression in osteogenic differentiation and influence the expression of target genes associated with osteogenic differentiation and ultimately regulate bone formation. The consequences of biophysical stimulation on osteogenic differentiation validate the prospect of exercise for the prevention and treatment of osteoporosis. In this review, we tend to summarize the studies on regulation of osteogenic differentiation by ncRNAs beneath biophysical stimulation and facilitate to reveal the regulatory mechanism of biophysical stimulation on ncRNAs, and provide an update for the prevention of bone metabolism diseases by exercise. [ABSTRACT FROM AUTHOR]

Knowledge regarding the relationship between the molecular mechanisms underlying atherosclerosis (AS) and transfer RNA‐derived small RNAs (tsRNAs) is limited. This study illustrated the expression profile of tsRNAs, thus exploring its roles in AS pathogenesis. Small RNA sequencing was performed with four atherosclerotic arterial and four healthy subject samples. Using bioinformatics, the protein‐protein interaction network and cellular experiments were constructed to predict the enriched signalling pathways and regulatory roles of tsRNAs in AS. Of the total 315 tsRNAs identified to be dysregulated in the AS group, 131 and 184 were up‐regulated and down‐regulated, respectively. Interestingly, the pathway of the differentiated expression of tsRNAs in cell adhesion molecules (CAMs) was implicated to be closely associated with AS. Particularly, tRF‐Gly‐GCC might participate in AS pathogenesis via regulating cell adhesion, proliferation, migration and phenotypic transformation in HUVECs and VSMCs. In conclusion, tsRNAs might help understand the molecular mechanisms of AS better. tRF‐Gly‐GCC may be a promising target for suppressing abnormal vessels functions, suggesting a novel strategy for preventing the progression of atherosclerosis. [ABSTRACT FROM AUTHOR]

Numerous factors influence breast cancer (BC) prognosis, thus complicating the prediction of outcome. By identifying biomarkers that would distinguish the cases with poorer response to therapy already at the time of diagnosis, the rate of survival could be improved. Lately, Piwi‐interacting RNAs (piRNAs) have been introduced as potential cancer biomarkers, however, due to the recently raised challenges in piRNA annotations, further evaluation of piRNAs' involvement in cancer is required. We performed small RNA sequencing in 227 fresh‐frozen breast tissue samples from the Eastern Finnish Kuopio Breast Cancer Project material to study the presence of piRNAs in BC and their associations with the clinicopathological features and outcome of BC patients. We observed the presence of three small RNAs annotated as piRNA database entries (DQ596932, DQ570994, and DQ571955) in our samples. The actual species of these RNAs however remain uncertain. All three small RNAs were upregulated in grade III tumors and DQ596932 additionally in estrogen receptor negative tumors. Furthermore, patients with estrogen receptor positive BC and higher DQ571955 had shorter relapse‐free survival and poorer BC‐specific survival, thus indicating DQ571955 as a candidate predictive marker for radiotherapy response in estrogen receptor positive BC. DQ596932 showed possible prognostic value in BC, whereas DQ570994 was identified as a candidate predictive marker for tamoxifen and chemotherapy response. These three small RNAs appear as candidate biomarkers for BC, which could after further investigation provide novel approaches for the treatment of therapy resistant BC. Overall, our results indicate that the prevalence of piRNAs in cancer is most likely not as comprehensive as has been previously thought. [ABSTRACT FROM AUTHOR]

Approaches to induce tumor differentiation often result in manageable and therapy‐naïve cellular states in cancer cells. This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non‐coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic regimen in one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely resulting from heterogeneity in the genetic and physiological landscapes of tumor types necessitating an approach designed for each cancer's unique genetic and phenotypic build‐up. [ABSTRACT FROM AUTHOR]

Aging is a biological process caused by the accumulation of senescent cells with a permanent proliferative arrest. To the influence of aging on human life expectancy, there is essential for new biomarkers which possibly will assistance in recognizing age‐associated pathologies. Exosomes, which are cell‐secreted nanovesicles, make available a new biomarker detection and therapeutic approach for the transfer of different molecules with high capacity. Recently, non‐coding RNAs (ncRNA) which are contained in exosomes have developed as important molecules regulating the complexity of aging and relevant human diseases. The discovery of ncRNA provided perceptions into an innovative regulatory platform that could interfere with cellular senescence. The non‐coding transcriptome includes a different of RNA species, spanning from short ncRNAs (<200 nucleotides) to long ncRNAs, that are >200 bp long. Upgraded evidence displays that targeting ncRNAs possibly will influence senescence pathways. In this article, we will address ncRNAs that participated in age‐related and cellular senescence diseases. Growing conception of ncRNAs in the aging process possibly will be responsible for new understandings into the improvement of age‐related diseases and elongated life span. [ABSTRACT FROM AUTHOR]

Background: As a type of head and neck squamous cell carcinoma (HNSCC), oral squamous cell carcinoma (OSCC) has a high incidence and low survival rate. Frequent deletion of protein tyrosine phosphatase receptor type sigma (PTPRS) has been found in HNSCC. Long non‐coding RNA (lncRNA) HCG11 and miR‐455‐5p have been reported to be involved in several cancers, in which miR‐455‐5p was found to be up‐regulated in the OSCC. However, the role of HCG11 in OSCC development is still unclear. Methods: Several co‐transfection systems were established to explore the regulation of HCG11 on OSCC cells. Cell proliferation was evaluated by the MTT assay, flow cytometry of cell cycle distribution, immunofluorescence of Ki67 and western blotting. A dual luciferase reporter assay was performed to verify the binding effects of miR‐455‐5p on HCG11 and PTPRS. The role of HCG11 knockdown in OSCC cell growth was also confirmed by nude mouse tumorigenicity assay in vivo. Results: Knockdown of HCG11 increased OSCC cell proliferation, as indicated by enhanced cell vitalities over time, increased G1/S transition and Ki67 levels. Furthermore, lncRNA HCG11 was shown to negatively regulate miR‐455‐5p and miR‐455‐5p targeted PTPRS directly to affect its downstream indicators, which can further modulate OSCC cell proliferation and growth. The results obtained in vivo confirmed that HCG11 knockdown promoted OSCC cell growth. Conclusions: The lncRNA HCG11/miR‐R‐455‐5p axis can be considered as an upstream signalling circuit of PTPRS with respect to regulating its activity and downstream pathways to further influence the progression of OSCC. This finding may provide a novel RNA‐based therapeutic target for OSCC treatment. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are associated with high incidence and mortality, contribute to disability and place a heavy economic burden on countries worldwide. Stimulating endogenous cardiomyocyte proliferation and regeneration has been considering as a key to repair the injured heart caused by ischaemia. Emerging evidence has proved that non‐coding RNAs participate in cardiac proliferation and regeneration. In this review, we focus on the observation and mechanism that microRNAs (or miRNAs), long non‐coding RNAs (or lncRNAs) and circular RNA (or circRNAs) regulate cardiomyocyte proliferation and regeneration to repair a damaged heart. Furthermore, we highlight the potential therapeutic role of some non‐coding RNAs used in stimulating CMs proliferation. Finally, perspective on the development of non‐coding RNAs therapy in cardiac regeneration is presented. [ABSTRACT FROM AUTHOR]

Cleft lip (CL) with/without cleft palate (CP) (hereafter CL/P) is the second most common congenital birth defect, affecting 7.94 to 9.92 children per 10 000 live births worldwide, followed by Down syndrome. An increasing number of genes have been identified as affecting susceptibility and/or as causative genes for CL/P in mouse genetic and chemically induced CL and CP studies, as well as in human genome‐wide association studies and linkage analysis. While marked progress has been made in the identification of genetic and environmental risk factors for CL/P, the interplays between these factors are not yet fully understood. This review aims to summarize our current knowledge of CL and CP from genetically engineered mouse models and environmental factors that have been studied in mice. Understanding the regulatory mechanism(s) of craniofacial development may not only advance our understanding of craniofacial developmental biology, but could also provide approaches for the prevention of birth defects and for tissue engineering in craniofacial tissue regeneration. [ABSTRACT FROM AUTHOR]

Despite the substantial progress in multiple myeloma (MM) therapy nowadays, treatment resistance and disease relapse remain major clinical hindrances. Herein, we have investigated tRNA-derived fragment (tRF) profiles in MM and precursor stages (smoldering MM/sMM; monoclonal gammopathy of undetermined significance/MGUS), aiming to unveil potential MM-related tRFs in ameliorating MM prognosis and risk stratification. Small RNA-seq was performed to profile tRFs in bone marrow CD138 + plasma cells, revealing the significant deregulation of the mitochondrial internal tRF HisGTG (mt-i-tRF HisGTG ) in MM versus sMM/MGUS. The screening cohort of the study consisted of 147 MM patients, and mt-i-tRF HisGTG levels were quantified by RT-qPCR. Disease progression was assessed as clinical end-point for survival analysis, while internal validation was performed by bootstrap and decision curve analyses. Screening cohort analysis highlighted the potent association of reduced mt-i-tRF HisGTG levels with patients' bone disease (p = 0.010), osteolysis (p = 0.023) and with significantly higher risk for short-term disease progression following first-line chemotherapy, independently of patients' clinical data (HR = 1.954; p = 0.036). Additionally, mt-i-tRF HisGTG -fitted multivariate models led to superior risk stratification of MM patients' treatment outcome and prognosis compared to disease-established markers. Notably, our study highlighted mt-i-tRF HisGTG loss as a powerful independent indicator of post-treatment progression of MM patients, leading to superior risk stratification of patients' treatment outcome., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Aortic dissection (AD) is the rupture of the aortic intima, causing the blood in the cavity to enter the middle of the arterial wall. Without urgent and proper treatment, the mortality rate increases to 50% within 48 hours. Most patients present with acute onset of symptoms, including sudden severe pain and complex and variable clinical manifestations, which can be easily misdiagnosed. Despite this, the molecular mechanisms underlying AD are still unknown. Recently, non‐coding RNAs have emerged as novel regulators of gene expression. Previous studies have proven that ncRNAs can regulate several cardiovascular diseases; therefore, their potential as clinical biomarkers and novel therapeutic targets for AD has aroused widespread interest. To date, several studies have reported that microRNAs are crucially involved in AD progression. Additionally, several long non‐coding RNAs and circular RNAs have been found to be differentially expressed in AD samples, suggesting their potential roles in vascular physiology and disease. In this review, we discuss the functions of ncRNAs in AD pathophysiology and highlight their potential as biomarkers and therapeutic targets for AD. Meanwhile, we present the animal models previously used for AD research, as well as the specific methods for constructing mouse or rat AD models. [ABSTRACT FROM AUTHOR]

SUMMARY: Ripening of tomato fruit is a complex tightly orchestrated developmental process that involves multiple physiological and metabolic changes that render fruit attractive, palatable and nutritious. Ripening requires initiation, activation and coordination of key pathways at the transcriptional and post‐transcriptional levels that lead to ethylene synthesis and downstream ripening events determining quality. We studied wild‐type, Gr and r mutant fruits at the coding and non‐coding transcriptomic, metabolomic and genome methylation levels. Numerous differentially expressed non‐coding RNAs were identified and quantified and potential competing endogenous RNA regulation models were constructed. Multiple changes in gene methylation were linked to the ethylene pathway and ripening processes. A combined analysis of changes in genome methylation, long non‐coding RNAs, circular RNAs, micro‐RNAs and fruit metabolites revealed many differentially expressed genes (DEGs) with differentially methylated regions encoding transcription factors and key enzymes related to ethylene or carotenoid pathways potentially targeted by differentially expressed non‐coding RNAs. These included ACO2 (targeted by MSTRG.59396.1 and miR396b), CTR1 (targeted by MSTRG.43594.1 and miR171b), ERF2 (targeted by MSTRG.183681.1), ERF5 (targeted by miR9470‐3p), PSY1 (targeted by MSTRG.95226.7), ZISO (targeted by 12:66127788|66128276) and NCED (targeted by MSTRG.181568.2). Understanding the functioning of this intricate genetic regulatory network provides new insights into the underlying integration and relationships between the multiple events that collectively determine the ripe phenotype. Significance Statement: Understanding the functioning of the intricate genetic regulatory network behind tomato fruit ripening provides new insights into the underlying integration and relationships between the multiple events that collectively determine the ripe phenotype. [ABSTRACT FROM AUTHOR]

After transcription, a messenger RNA (mRNA) is further post‐transcriptionally regulated by several features including RNA secondary structure and covalent RNA modifications (specifically N6‐methyladenosine, m6A). Both RNA secondary structure and m6A have been demonstrated to regulate mRNA stability and translation and have been independently linked to plant responses to soil salinity levels. However, the effect of m6A on regulating RNA secondary structure and the combinatorial interplay between these two RNA features during salt stress response has yet to be studied. Here, we globally identify RNA‐protein interactions and RNA secondary structure during systemic salt stress. This analysis reveals that RNA secondary structure changes significantly during salt stress, and that it is independent of global changes in RNA‐protein interactions. Conversely, we find that m6A is anti‐correlated with RNA secondary structure in a condition‐dependent manner, with salt‐specific m6A correlated with a decrease in mRNA secondary structure during salt stress. Taken together, we suggest that salt‐specific m6A deposition and the associated loss of RNA secondary structure results in increases in mRNA stability for transcripts encoding abiotic stress response proteins and ultimately increases in protein levels from these stabilized transcripts. In total, our comprehensive analyses reveal important post‐transcriptional regulatory mechanisms involved in plant long‐term salt stress response and adaptation. [ABSTRACT FROM AUTHOR]

Various species of non‐coding RNAs (ncRNAs) are enriched in specific subcellular compartments, but the mechanisms orchestrating their localization and their local functions remain largely unknown. We investigated both aspects using the elongating retinal ganglion cell axon and its tip, the growth cone, as models. We reveal that specific endogenous precursor microRNAs (pre‐miRNAs) are actively trafficked to distal axons by hitchhiking primarily on late endosomes/lysosomes. Upon exposure to the axon guidance cue semaphorin 3A (Sema3A), pre‐miRNAs are processed specifically within axons into newly generated miRNAs, one of which, in turn, silences the basal translation of tubulin beta 3 class III (TUBB3), but not amyloid beta precursor protein (APP). At the organismal level, these mature miRNAs are required for growth cone steering and a fully functional visual system. Overall, our results uncover a novel mode of ncRNA transport from one cytosolic compartment to another within polarized cells. They also reveal that newly generated miRNAs are critical components of a ncRNA‐based signaling pathway that transduces environmental signals into the structural remodeling of subcellular compartments. Synopsis: Mechanisms regulating subcellular localization and local function of non‐coding RNA are not well understood. Here, neuronal pre‐miRNAs are found to traffic along axons docked to endosomes, with axonal processing of pre‐miRNAs leading to the inhibition of local protein synthesis. Precursor miRNAs hitchhike onto late endosomes/lysosomes to reach the growth cone.Sema3A, but not Slit2, axon guidance cue induces local biogenesis of specific miRNAs within axons.Newly generated miRNAs inhibit basal translation of TUBB3 but not APP upon Sema3A exposure.miRNAs regulate growth cone steering and the establishment of functional connections. [ABSTRACT FROM AUTHOR]

Scoliosis, a complex three‐dimensional deformity of the spine with the Cobb angle (a measure of the spinal lateral curvature) >10 degree, encompasses a spectrum of pathologies, including congenital, idiopathic, syndromic and neuromuscular aetiologies. The pathogenesis is multifactorial involving both environmental and genetic factors but the exact cellular and molecular mechanisms of disease development remain largely unknown. Emerging evidence showed that non‐coding RNAs (ncRNAs), namely microRNAs, long ncRNAs and circular RNAs, are deregulated in many orthopaedic diseases, including scoliosis. Importantly, these deregulated ncRNAs functionally participate in the initiation and progression of scoliosis. Here, we review recent progress in ncRNA research on scoliosis. [ABSTRACT FROM AUTHOR]

• Epigenetic studies involving paternal drug exposures are in their infancy. • Paternal drug exposure has long-lasting consequences in offspring. • Epigenetic changes in the germ line associate with behavioral abnormalities. • Information about epigenetic processes may yield novel therapeutic approaches. Substance use disorders (SUDs) reflect genetic and environmental factors. While identifying reliable genetic variants that predispose individuals to developing SUDs has been challenging, epigenetic factors may also contribute to the heritability of SUDs. Familial drug use associates with a wide range of problems in children, including an increased risk for developing a SUD. The implications of maternal drug use on offspring development are a well-studied area; however, paternal drug use prior to conception has received relatively little attention. Paternal exposure to several environmental stimuli (i.e. stress or diet manipulations) results in behavioral and epigenetic changes in offspring. The purpose of this review is to determine the state of the preclinical literature on the behavioral and epigenetic consequences of paternal drug exposure. Drug-sired offspring show several developmental and physiological abnormalities. These offspring also show deficits in cognitive and emotional domains. Examining sensitivity to drugs in offspring is a growing area of research. Drug-sired offspring are resistant to the rewarding and reinforcing properties of drugs. However, greater paternal motivation for the drug, combined with high drug intake, can result in addiction-like behaviors in offspring. Drug-sired offspring also show altered histone modifications and DNA methylation levels of imprinted genes and microRNAs; epigenetic-mediated changes were also noted in genes related to glutamatergic and neurotrophic factor signaling. In some instances, drug use resulted in aberrant epigenetic modifications in sire sperm, and these changes were maintained in the brains of offspring. Thus, paternal drug exposure has long-lasting consequences that include altered drug sensitivity in subsequent generations. We discuss factors (i.e. maternal behaviors) that may moderate these paternal drug-induced effects as well as ideas for future directions. [ABSTRACT FROM AUTHOR]

Nucleic acids epigenetic modifications including DNA and RNA methylation and post transcriptional gene regulation by noncoding RNAs (ncRNAs) such as microRNAs and long ncRNAs (lncRNAs), are of great relevance due to their role in mammalian development and the initiation and progression of various diseases like cancer. Over the past decades, a great research effort was made for determining nucleic acid methylation, electrochemical biosensors rapidly developing as efficient analytical tools for the determination of epigenetic modification of nucleic acids. In this review article, a critical overview of recently reported advances in their development and use for the determination of epigenetic modifications of nucleic acids, including the presence of methylated bases in DNA and RNA and the aberrant expression of microRNAs and lncRNAs, is provided. Special emphasis is made on methodologies successfully applied to real clinical samples, unmet challenges or key points toward future research. [ABSTRACT FROM AUTHOR]

• Stem cell-based transplantation strategy possesses significant role in repairing spinal cord injury. • Chitosan scaffolds enhance the adhesion, proliferation and neural differentiation of grafted stem cells in vitro and in vivo. • Application of chitosan could up-regulate neurotrophic factors which are beneficial to repair of spinal cord injury. • Scaffolds and carriers prepared by chitosan could sustain release of neurotrophic factors/RNAs for a long time. Cytology and histology obstacles have been the main barriers to multiple tissues injury repair. In search of the most promising treatment strategies for spinal cord injury (SCI), stem cell-based transplantation coupled with various materials/technologies have been explored extensively to enhance SCI repair. Chitosan (CS) has demonstrated immense potential for widespread application in the form of scaffolds and micro-particles for SCI repair. The current review summarizes the evidences for stem cell-based transplantation and CS in SCI repair. Stem cells transplantation, which plays a key role in the repair of SCI, mainly results from its neural differentiation potential and neurotrophic effects. Application of CS enhances the survival of grafted stem cells, upregulates the expression level of neurotrophic factors and heightens the neural differentiation of stem cells as well as the functional recovery of spinal cord. Meanwhile, CS can also be exploited as growth factors/RNA carriers to control the release of regenerating molecules which are beneficial to damage spinal cord repair. [ABSTRACT FROM AUTHOR]

Abstract: The molecular roles of the dually targeted ElaC domain protein 2 (ELAC2) during nuclear and mitochondrial RNA processing in vivo have not been distinguished. We generated conditional knockout mice of ELAC2 to identify that it is essential for life and its activity is non‐redundant. Heart and skeletal muscle‐specific loss of ELAC2 causes dilated cardiomyopathy and premature death at 4 weeks. Transcriptome‐wide analyses of total RNAs, small RNAs, mitochondrial RNAs, and miRNAs identified the molecular targets of ELAC2 in vivo. We show that ELAC2 is required for processing of tRNAs and for the balanced maintenance of C/D box snoRNAs, miRNAs, and a new class of tRNA fragments. We identify that correct biogenesis of regulatory non‐coding RNAs is essential for both cytoplasmic and mitochondrial protein synthesis and the assembly of mitochondrial ribosomes and cytoplasmic polysomes. We show that nuclear tRNA processing is required for the balanced production of snoRNAs and miRNAs for gene expression and that 3′ tRNA processing is an essential step in the production of all mature mitochondrial RNAs and the majority of nuclear tRNAs. [ABSTRACT FROM AUTHOR]

Abstract: In our recent cDNA microarray experiment, three SR‐rich splicing factors—SFRS18, PPIG and LUC7L3—were shown to exert altered responsiveness upon T‐lymphokine stimulation of psoriatic non‐involved and healthy epidermis samples. We have also demonstrated that double silencing LUC7L3 and SFRS18 efficiently decreased production of the psoriasis‐associated EDA+ fibronectin isoform. These findings prompted the further investigation of signalling pathways affected by LUC7L3 and SFRS18. To detect gene expression and splicing pattern alterations upon double silencing of LUC7L3 and SFRS18 in an HPV‐immortalised keratinocyte cell culture, paired‐end RNA sequencing was carried out. Marked changes in exon usage were revealed, in contrast to the modest alterations detected in gene expression, providing a closer delineation of the potential targets of the examined splicing factors. The most prominent gene expression change was detected for IFI6, an interferon‐inducible gene highly expressed in psoriasis. Interacting partners of IFI6 and certain psoriasis‐associated transcripts also exhibited significantly increased expression upon silencing. In addition to elevated abundance of the EDA+ fibronectin interactor ITGA5, we confirmed decreased EDA domain inclusion, which agrees well with our prior experimental data. Furthermore, differential exon usage was established for the transcription element CREB1, along with HERC6 and CUL1, which are implicated in ubiquitination. Although immortalised keratinocytes express low levels of TINCR, a long non‐coding RNA involved in terminal differentiation of keratinocytes, splicing alterations were successfully demonstrated for this RNA as well. We believe that the targeted investigation of mRNA maturation disturbances may help us gain deeper insight into the molecular pathogenesis of psoriasis. [ABSTRACT FROM AUTHOR]

Piwi-interacting RNAs (pi RNAs), a novel class of small non-coding RNAs, were first discovered in germline cells and are thought to silence transposons in spermatogenesis. Recently, pi RNAs have also been identified in somatic tissues, and aberrant expression of pi RNAs in tumor tissues may be implicated in carcinogenesis. However, the function of piR-823 in colorectal cancer ( CRC) remains unclear. Here, we first found that piR-823 was significantly upregulated in CRC tissues compared with its expression in the adjacent tissues. Inhibition of piR-823 suppressed cell proliferation, arrested the cell cycle in the G1 phase and induced cell apoptosis in CRC cell lines HCT116 and DLD-1, whereas overexpression of piR-823 promoted cell proliferation in normal colonic epithelial cell line FHC. Interestingly, Inhibition of piR-823 repressed the expression of heat shock protein ( HSP) 27, 60, 70. Furthermore, elevated HSPs expression partially abolished the effect of piR-823 on cell proliferation and apoptosis. In addition, we further demonstrated that piR-823 increased the transcriptional activity of HSF1, the common transcription factor of HSPs, by binding to HSF1 and promoting its phosphorylation at Ser326. Our study reveals that piR-823 plays a tumor-promoting role by upregulating phosphorylation and transcriptional activity of HSF1 and suggests piR-823 as a potential therapeutic target for CRC. [ABSTRACT FROM AUTHOR]

Cardiovascular disease, and particularly heart failure, is still a serious health care issue for which novel treatments and biomarkers are needed. The RNA family comprises different subgroups, among which the small-sized microRNAs and the larger long non-coding RNAs have shown some potential to aid in moving personalized health care of heart failure patients a step forward. Here, members of the Cardiolinc network review the recent findings suggesting that the less well-known circular RNAs may constitute a novel reservoir of therapeutic targets and biomarkers of heart failure. The knowledge of the mode of biogenesis of circular RNAs will first be reported, followed by a description of different features that make these RNA molecules of interest for the heart failure community. The functions of circular RNAs in the heart will be described, with some emphasis given to their regulation in the failing heart. Circulating in the bloodstream, circular RNAs have appeared as potential biomarkers and recent findings associated with the use of circular RNAs as heart failure biomarkers will be discussed. Finally, some directions for future research will be provided. [ABSTRACT FROM AUTHOR]

Contents22I.22II.24III.25IV.27V.29VI.1031References32 Summary: Plants have evolved a remarkable faculty of adaptation to deal with various and changing environmental conditions. In this context, the roots have taken over nutritional aspects and the root system architecture can be modulated in response to nutrient availability or biotic interactions with soil microorganisms. This adaptability requires a fine tuning of gene expression. Indeed, root specification and development are highly complex processes requiring gene regulatory networks involved in hormonal regulations and cell identity. Among the different molecular partners governing root development, microRNAs (miRNAs) are key players for the fast regulation of gene expression. miRNAs are small RNAs involved in most developmental processes and are required for the normal growth of organisms, by the negative regulation of key genes, such as transcription factors and hormone receptors. Here, we review the known roles of miRNAs in root specification and development, from the embryonic roots to the establishment of root symbioses, highlighting the major roles of miRNAs in these processes. [ABSTRACT FROM AUTHOR]

The ability of the classic tumour-suppressive let-7 family to inhibit carcinogenesis, tumour progression, recurrence and pluripotency of cancer stem cells has generated significant interest in the field of cancer research. Through suppressing and degrading downstream-targeted mRNAs, let-7 affected most aspects of cell biology. It is perplexing how let-7 affects oncogenesis, as the large influx of new mi RNAs and other kinds of non-coding RNAs are continuously defined. In this review, we delineate the complex functions of let-7 and discuss the future direction of let-7 research. [ABSTRACT FROM AUTHOR]

Metastasis is the primary cause of death in prostate cancer (PCa) patients. Small nucleolar RNAs (snoRNAs) have long been considered “housekeeping” genes with no relevance for cancer biology. Emerging evidence has challenged this assumption, suggesting that snoRNA expression is frequently modulated during cancer progression. Despite this, no study has systematically addressed the prognostic and functional significance of snoRNAs in PCa. We performed RNA Sequencing on paired metastatic/non-metastatic PCa xenografts derived from clinical specimens. The clinical significance of differentially expressed snoRNAs was further investigated in two independent primary PCa cohorts (131 and 43 patients, respectively). The snoRNA demonstrating the strongest association with clinical outcome was quantified in PCa patient-derived serum samples and its functional relevance was investigated in PCa cells via gene expression profiling, pathway analysis and gene silencing. Our comparison revealed 21 differentially expressed snoRNAs in the metastatic vs. non-metastatic xenografts. Of those, 12 were represented in clinical databases and were further analyzed. SNORA55 emerged as a predictor of shorter relapse-free survival (results confirmed in two independent databases). SNORA55 was reproducibly detectable in serum samples from PCa patients. SNORA55 silencing in PCa cell lines significantly inhibited cell proliferation and migration. Pathway analysis revealed that SNORA55 expression is significantly associated with growth factor signaling and pro-inflammatory cytokine expression in PCa. Our results demonstrate that SNORA55 up-regulation predicts PCa progression and that silencing this non-coding gene affects PCa cell proliferation and metastatic potential, thus positioning it as both a novel biomarker and therapeutic target. [ABSTRACT FROM AUTHOR]

Cancer stem cells ( CSCs) are linked to metastasis. Moreover, a discrete group of mi RNAs (metastamiRs) has been shown to promote metastasis. Accordingly, we propose that mi RNAs that function as metastatic promoters may influence the CSC phenotype. To study this issue, we compared the expression of 353 mi RNAs in CSCs enriched from breast cancer cell lines using qRT- PCR analysis. One of the most altered mi RNAs was miR-10b, which is a reported promoter of metastasis and migration. Stable overexpression of miR-10b in MCF-7 cells (miR-10b-OE cells) promoted higher self-renewal and expression of stemness and epithelial-mesenchymal transition ( EMT) markers. In agreement with these results, inhibiting miR-10b expression using synthetic antisense RNAs resulted in a decrease in CSCs self-renewal. Bioinformatics analyses identified several potential miR-10b mRNA targets, including phosphatase and tensin homolog ( PTEN), a key regulator of the PI3K/ AKT pathway involved in metastasis, cell survival, and self-renewal. The targeting of PTEN by miR-10b was confirmed using a luciferase reporter, qRT- PCR, and Western blot analyses. Lower PTEN levels were observed in CSCs, and miR-10b depletion not only increased PTEN mRNA and protein expression but also decreased the activity of AKT, a downstream PTEN target kinase. Correspondingly, PTEN knockdown increased stem cell markers, whereas AKT inhibitors compromised the self-renewal ability of CSCs and breast cancer cell lines overexpressing miR-10b. In conclusion, miR-10b regulates the self-renewal of the breast CSC phenotype by inhibiting PTEN and maintaining AKT pathway activation. [ABSTRACT FROM AUTHOR]

Hirschsprung's disease ( HSCR), a birth defect characterized by variable aganglionosis of the gut, affects about 1 in 5000 births and is a consequence of abnormal development of neural crest cells, from which enteric ganglia derive. In the companion article in this issue (Shen et al., Neurogasterenterol Motil 28: 266-73), the authors search for long non-coding RNAs (lnc RNAs) differentially expressed in bowel tissues of infants with HSCR. Microarray analysis of over 37 000 lnc RNAs and 34 000 mRNAs was done. The key result was identification of a set of 5 lnc RNAs that is a potential diagnostic biomarker of HSCR. In this minireview, I provide an overview of neural crest development and the gene regulatory networks involved in specification, epithelial-mesenchymal transition, and migration of neural crest cells. Genes involved in later development, proliferation, and differentiation of neural crest cells as they migrate into the gut are also reviewed. Many of these genes are associated with HSCR, including RET, GDNF, GFR α, EDN3, and EDNRB. Lnc RNAs and their roles in development and disease and their use as biomarkers are discussed. The authors of the companion article previously used a multipronged approach to elucidate the etiology of HSCR by examining the effects of specific mi RNAs or lnc RNAs and target genes on cell migration, proliferation, cell cycle, and apoptosis in vitro. These studies are discussed in terms of their elegance and limitations. The companion article identifies many new lnc RNAs that, in addition to providing potential biomarkers of HSCR, may be a treasure trove for future investigations. [ABSTRACT FROM AUTHOR]

Until recently, retention of introns in mature mRNAs has been regarded as a consequence of mis-splicing. Intronretaining transcripts are thought to be non-functional because they are readily degraded by nonsense-mediated decay. However, recent advances in next-generation sequencing technologies have enabled the detection of numerous transcripts that retain introns. As we review herein, intron-retaining mRNAs play an essential conserved role in normal physiology and an emergent role in diverse diseases. Intron retention should no longer be overlooked as a key mechanism that independently reduces gene expression in normal biology. Exploring its contribution to the development and/or maintenance of diseases is of increasing importance. [ABSTRACT FROM AUTHOR]

Maintenance of vascular integrity is essential for the prevention of vascular disease and for recovery following cardiovascular, cerebrovascular and peripheral vascular events including limb ischemia, heart attack and stroke. Endothelial stem/progenitor cells have recently gained considerable interest due to their potential use in stem cell therapies to mediate revascularization after ischemic injury. Therefore, there is an urgent need to understand fundamental mechanisms regulating vascular repair in specific cell types to develop new beneficial therapeutic interventions. In this review, we highlight recent studies demonstrating that epigenetic mechanisms (including post-translational modifications of DNA and histones as well as non-coding RNA-mediated processes) play essential roles in the regulation of endothelial stem/progenitor cell functions through modifying chromatin structure. Furthermore, we discuss the potential of using small molecules that modulate the activities of epigenetic enzymes to enhance the vascular repair function of endothelial cells and offer insight on potential strategies that may accelerate clinical applications. [ABSTRACT FROM AUTHOR]

Identifying all essential genomic components is critical for the assembly of minimal artificial life. In the genome-reduced bacterium Mycoplasma pneumoniae, we found that small ORFs (sm ORFs; < 100 residues), accounting for 10% of all ORFs, are the most frequently essential genomic components (53%), followed by conventional ORFs (49%). Essentiality of sm ORFs may be explained by their function as members of protein and/or DNA/ RNA complexes. In larger proteins, essentiality applied to individual domains and not entire proteins, a notion we could confirm by expression of truncated domains. The fraction of essential non-coding RNAs (nc RNAs) non-overlapping with essential genes is 5% higher than of non-transcribed regions (0.9%), pointing to the important functions of the former. We found that the minimal essential genome is comprised of 33% (269,410 bp) of the M. pneumoniae genome. Our data highlight an unexpected hidden layer of sm ORFs with essential functions, as well as non-coding regions, thus changing the focus when aiming to define the minimal essential genome. [ABSTRACT FROM AUTHOR]

The article discusses a study on epigenomic networking in drug development, along with pathogenic mechanisms to pharmacogenomics. Topics include the relationship between different epigenetic alterations and the phenotypic expression of complex disorders, the efficacy and safety issues in clinical trials with epigenetic drugs, and the epigenetic modifications.

Small non-protein coding RNAs (ncRNAs) play important roles in development, stress response and other cellular processes. Silkworm is an important model for studies on insect genetics and control of Lepidopterous pests. We have previously identified 189 novel intermediate-size ncRNAs in silkworm Bombyx mori, including 40 ncRNAs that showed altered expression in different developmental stages. Here we characterized the functions of these 40 ncRNAs by measuring their expressions in six tissues of the fifth instar larvae using Northern blot and real-time polymerase chain reaction assays. We identified nine ncRNAs (four small nucleolar RNAs and five unclassified ncRNAs) that were enriched in silk gland, including four ncRNAs that showed silk gland-specific expression. We further showed that three of nine silk gland-enriched ncRNAs were predominantly expressed in the anterior silk gland, whereas another three ncRNAs were highly accumulated in the posterior silk gland, suggesting that they may play different roles in fibroin synthesis. Furthermore, an unclassified ncRNA, Bm-152, exhibited converse expression pattern with its antisense host gene gartenzwerg in diverse tissues, and might regulate the expression of gartenzwerg through RNA-protein complex. In addition, two silk gland-enriched ncRNAs Bm-102 and Bm-159 can be found in histone modification complex, which indicated that they might play roles through epigenetic modifications. Taken together, we provided the first expression and preliminary functional analysis of silk gland-enriched ncRNAs, which will help understand the molecular mechanism of silk gland-development and fibroin synthesis. [ABSTRACT FROM AUTHOR]

The world of non-coding RNAs has only recently started being discovered. For the past 40 years, coding genes, mRNA, and proteins have been the center of cellular and molecular biology, and pathologic alterations were attributed to either the aberration of gene sequence or altered promoter activity. It was only after the completion of the human genome sequence that the scientific community started seriously wondering why only a very small portion of the genome corresponded to protein-coding genes. New technologies such as the whole-genome and whole-transcriptome sequencing demonstrated that at least 90% of the genome is actively transcribed. The identification and cataloguing of multiple kinds of non-coding RNA (ncRNA) have exponentially increased, and it is now widely accepted that ncRNAs play major biological roles in cellular physiology, development, metabolism, and are also implicated in a variety of diseases. The aim of this review is to describe the two major classes (long and short forms) of non-coding RNAs and describe their subclasses in terms of function and their relevance and potential in oral diseases. [ABSTRACT FROM AUTHOR]

Epigenetics is commonly defined as the study of heritable changes in gene function that cannot be explained by changes in DNA sequence. The three major epigenetic mechanisms for gene expression regulation include DNA methylation, histone modifications, and non-coding RNAs. Epigenetic mechanisms provide organisms with the ability to integrate genomic and environmental information to modify the activity of their genes for generating a particular phenotype. During development, cells differentiate, acquire, and maintain identity through changes in gene expression. This is crucial for sex determination and differentiation, which are among the most important developmental processes for the proper functioning and perpetuation of species. This review summarizes studies showing how epigenetic regulatory mechanisms contribute to sex determination and reproductive organ formation in plants, invertebrates, and vertebrates. Further progress will be made by integrating several approaches, including genomics and Next Generation Sequencing to create epigenetic maps related to different aspects of sex determination and gonadogenesis. Epigenetics will also contribute to understand the etiology of several disorders of sexual development. It also might play a significant role in the control of reproduction in animal farm production and will aid in recognizing the environmental versus genetic influences on sex determination of sensitive species in a global change scenario. Developmental Dynamics 242:360-370, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]