Differential Expression Of Non-coding RNAs Research Articles

The intricate dance of non-coding RNAs in myasthenia gravis pathogenesis and treatment.

Myasthenia gravis (MG) stands as a perplexing autoimmune disorder affecting the neuromuscular junction, driven by a multitude of antibodies targeting postsynaptic elements. However, the mystery of MG pathogenesis has yet to be completely uncovered, and its heterogeneity also challenges diagnosis and treatment. Growing evidence shows the differential expression of non-coding RNAs (ncRNAs) in MG has played an essential role in the development of MG in recent years. Remarkably, these aberrantly expressed ncRNAs exhibit distinct profiles within diverse clinical subgroups and among patients harboring various antibody types. Furthermore, they have been implicated in orchestrating the production of inflammatory cytokines, perturbing the equilibrium of T helper 1 cells (Th1), T helper 17 cells (Th17), and regulatory T cells (Tregs), and inciting B cells to generate antibodies. Studies have elucidated that certain ncRNAs mirror the clinical severity of MG, while others may hold therapeutic significance, showcasing a propensity to return to normal levels following appropriate treatments or potentially foretelling the responsiveness to immunosuppressive therapies. Notably, the intricate interplay among these ncRNAs does not follow a linear trajectory but rather assembles into a complex network, with competing endogenous RNA (ceRNA) emerging as a prominent hub in some cases. This comprehensive review consolidates the landscape of dysregulated ncRNAs in MG, briefly delineating their pivotal role in MG pathogenesis. Furthermore, it explores their promise as prospective biomarkers, aiding in the elucidation of disease subtypes, assessment of disease severity, monitoring therapeutic responses, and as novel therapeutic targets.

Differential Expression of Noncoding RNAs Revealed Enhancer RNA AC016735.2 as a Potential Pathogenic Marker of Congenital Microtia Patients.

Congenital microtia is a complex maxillofacial malformation with various risk factors. This study aimed to find potential pathogenic noncoding RNAs for congenital microtia patients. We collected 3 pairs of residual ear cartilage samples and corresponding normal ear cartilage samples from nonsyndromic congenital microtia patients for microarray experiments. The differentially expressed RNAs were screened, and enrichment analysis and correlation expression analysis were performed to elucidate the function of the differentially expressed genes (DEGs). We further investigated the most significantly differentially expressed long noncoding RNA (lncRNA), AC016735.2, through follow-up analyses including RT-qPCR and Western blotting, to validate its differential expression in residual ear cartilage compared with normal ear cartilage. SiRNA was designed to study the regulatory role of AC016735.2, and cell proliferation experiments were conducted to explore its impact on residual ear chondrocytes. Analysis of the microarray data revealed a total of 1079 differentially expressed RNAs, including 305 mRNAs and x lncRNAs, using a threshold of FC>1.5 and P<0.05 for mRNA, and FC>1.0 and P<0.05 for lncRNA. Enrichment analysis indicated that these genes are mainly involved in extracellular matrix regulation and embryonic development. AC016735.2 showed the highest differential expression among the eRNAs, being upregulated in residual ear cartilage. It acts in cis to regulate the nearby coding gene ZFP36L2, indirectly affecting downstream genes such as BMP4, TWSG1, COL2A1, and COL9A2. Significant differences were observed in the expression of lncRNAs and mRNAs between residual ear cartilage and normal auricular cartilage tissues in the same genetic background of congenital microtia. These differentially expressed lncRNAs and mRNAs may play crucial roles in the occurrence and development of microtia through pathways associated with extracellular matrix regulation and gastrulation. Particularly, AC016735.2, an eRNA acting in cis, could serve as a potential pathogenic noncoding gene.

Expression of overall survival-EMT-immune cell infiltration genes predict the prognosis of glioma

This study investigates the crucial role of immune- and epithelial-mesenchymal transition (EMT)-associated genes and non-coding RNAs in glioma development and diagnosis, given the challenging 5-year survival rates associated with this prevalent CNS malignant tumor. Clinical and RNA data from glioma patients were meticulously gathered from CGGA databases, and EMT-related genes were sourced from dbEMT2.0, while immune-related genes were obtained from MSigDB. Employing consensus clustering, novel molecular subgroups were identified. Subsequent analyses, including ESTIMATE, TIMER, and MCP counter, provided insights into the tumor microenvironment (TIME) and immune status. Functional studies, embracing GO, KEGG, GSVA, and GSEA analyses, unraveled the underlying mechanisms governing these molecular subgroups. Utilizing the LASSO algorithm and multivariate Cox regression, a prognostic risk model was crafted. The study unveiled two distinct molecular subgroups with significantly disparate survival outcomes. A more favorable prognosis was linked to low immune scores, high tumor purity, and an abundance of immune infiltrating cells with differential expression of non-coding RNAs, including miRNAs. Functional analyses illuminated enrichment of immune- and EMT-associated pathways in differentially expressed genes and non-coding RNAs between these subgroups. GSVA and GSEA analyses hinted at abnormal EMT status potentially contributing to glioma-associated immune disorders. The risk model, centered on OS-EMT-ICI genes, exhibited promise in accurately predicting survival in glioma. Additionally, a nomogram integrating the risk model with clinical characteristics demonstrated notable accuracy in prognostic predictions for glioma patients. In conclusion, OS-EMT-ICI gene and non-coding RNA expression emerges as a valuable indicator intricately linked to immune microenvironment dysregulation, offering a robust tool for precise prognosis prediction in glioma patients within the OBMRC framework.

Role of Epigenetic Factors in Response to Stress and Establishment of Somatic Memory of Stress Exposure in Plants.

All species are well adapted to their environment. Stress causes a magnitude of biochemical and molecular responses in plants, leading to physiological or pathological changes. The response to various stresses is genetically predetermined, but is also controlled on the epigenetic level. Most plants are adapted to their environments through generations of exposure to all elements. Many plant species have the capacity to acclimate or adapt to certain stresses using the mechanism of priming. In most cases, priming is a somatic response allowing plants to deal with the same or similar stress more efficiently, with fewer resources diverted from growth and development. Priming likely relies on multiple mechanisms, but the differential expression of non-coding RNAs, changes in DNA methylation, histone modifications, and nucleosome repositioning play a crucial role. Specifically, we emphasize the role of BRM/CHR17, BRU1, FGT1, HFSA2, and H2A.Z proteins as positive regulators, and CAF-1, MOM1, DDM1, and SGS3 as potential negative regulators of somatic stress memory. In this review, we will discuss the role of epigenetic factors in response to stress, priming, and the somatic memory of stress exposures.

Differential Expression of Non-Coding RNAs in Stem Cell Development and Therapeutics of Bone Disorders.

Stem cells' self-renewal and multi-lineage differentiation are regulated by a complex network consisting of signaling factors, chromatin regulators, transcription factors, and non-coding RNAs (ncRNAs). Diverse role of ncRNAs in stem cell development and maintenance of bone homeostasis have been discovered recently. The ncRNAs, such as long non-coding RNAs, micro RNAs, circular RNAs, small interfering RNA, Piwi-interacting RNAs, etc., are not translated into proteins but act as essential epigenetic regulators in stem cells' self-renewal and differentiation. Different signaling pathways are monitored efficiently by the differential expression of ncRNAs, which function as regulatory elements in determining the fate of stem cells. In addition, several species of ncRNAs could serve as potential molecular biomarkers in early diagnosis of bone diseases, including osteoporosis, osteoarthritis, and bone cancers, ultimately leading to the development of new therapeutic strategies. This review aims to explore the specific roles of ncRNAs and their effective molecular mechanisms in the growth and development of stem cells, and in the regulation of osteoblast and osteoclast activities. Furthermore, we focus on and explore the association of altered ncRNA expression with stem cells and bone turnover.

Differential expression of non-coding RNAs and association with cerebral ischemic vascular disorders; diagnostic and therapeutic opportunities.

Over the last few decades, research associated with the coding genome, primarily DNA and transcriptome (mRNA, rRNA, and tRNA), has changed our understanding in several aspects, including physiology, diagnostics, and therapeutics. A large proportion of the human genome that encodes proteins is essential for physiology. However, the human genome represents a significantly large proportion of non-translational, i.e., non-coding (nc) RNAs like microRNAs, siRNAs, piRNAs, lncRNAs, and circRNAs. These ncRNAs do not translate into functional proteins but are associated with several events, such as the regulation of gene expression via several mechanisms. Our understanding of ncRNAs has advanced in the last decade, such as microRNAs and siRNAs, but still, several other ncRNAs remain unexplored. The study comprehended the association of ncRNAs in cerebral ischemia. In this study searches utilizing multiple databases, PubMed, EMBASE, and Google Scholar were made. The literature survey was done on ncRNA including short and lncRNA associated with the onset, and progression of cerebral ischemia. The literature search was also made for the studies associated with the diagnostic and therapeutic role of ncRNAs for cerebral ischemia. Reports suggested that both short and long ncRNAs are critical players of gene expression and are hence associated with the pathophysiology of cerebral ischemia. The reports demonstrate ncRNAs precisely lncRNAs and microRNAs are not only associated with cerebral ischemia progression but also potential diagnostic and therapeutic candidates. This review is certainly helpful to understand the interplay of ncRNAs in understanding gene expression profile and pathophysiology of cerebral ischemia. These ncRNAs molecules show potential for diagnostic and therapeutic development.

Role of Non-coding RNAs in Axon Regeneration after Peripheral Nerve Injury.

Peripheral nerve injury (PNI) may lead to disability and neuropathic pain, which constitutes a substantial economic burden to patients and society. It was found that the peripheral nervous system (PNS) has the ability to regenerate after injury due to a permissive microenvironment mainly provided by Schwann cells (SCs) and the intrinsic growth capacity of neurons; however, the results of injury repair are not always satisfactory. Effective, long-distance axon regeneration after PNI is achieved by precise regulation of gene expression. Numerous studies have shown that in the process of peripheral nerve damage and repair, differential expression of non-coding RNAs (ncRNAs) significantly affects axon regeneration, especially expression of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). In the present article, we review the cellular and molecular mechanisms of axon regeneration after PNI, and analyze the roles of these ncRNAs in nerve repair. In addition, we discuss the characteristics and functions of these ncRNAs. Finally, we provide a thorough perspective on the functional mechanisms of ncRNAs in nervous injury repair, and explore the potential these ncRNAs offer as targets of nerve injury treatment.

Epigenetic Changes Associated With Exposure to Glyphosate-Based Herbicides in Mammals.

Glyphosate is a phosphonomethyl amino acid derivative present in a number of non-selective and systemic herbicides. During the last years the use of glyphosate-based herbicide (GBH) has been increasing exponentially around the world, including Argentina. This fact added to the detection of glyphosate, and its main metabolite, amino methylphosphonic acid (AMPA), in environmental matrices such as soil, sediments, and food, has generated great concern about its risks for humans, animals, and environment. During the last years, there were controversy and intense debate regarding the toxicological effects of these compounds associated with the endocrine system, cancer, reproduction, and development. The mechanisms of action of GBH and their metabolites are still under investigation, although recent findings have shown that they could comprise epigenetic modifications. These are reversible mechanisms linked to tissue-specific silencing of gene expression, genomic imprinting, and tumor growth. Particularly, glyphosate, GBH, and AMPA have been reported to produce changes in global DNA methylation, methylation of specific genes, histone modification, and differential expression of non-coding RNAs in human cells and rodents. Importantly, the epigenome could be heritable and could lead to disease long after the exposure has ended. This mini-review summarizes the epigenetic changes produced by glyphosate, GBHs, and AMPA in humans and rodents and proposes it as a potential mechanism of action through which these chemical compounds could alter body functions.

Epigenetic Mechanisms in Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a brain-gut axis disorder characterized by abdominal pain and altered bowel habits. IBS is a multifactorial, stress-sensitive disorder with evidence for familial clustering attributed to genetic or shared environmental factors. However, there are weak genetic associations reported with IBS and a lack of evidence to suggest that major genetic factor(s) contribute to IBS pathophysiology. Studies on animal models of stress, including early life stress, suggest a role for environmental factors, specifically, stress associated with dysregulation of corticotropin releasing factor and hypothalamus-pituitary-adrenal (HPA) axis pathways in the pathophysiology of IBS. Recent evidence suggests that epigenetic mechanisms, which constitute molecular changes not driven by a change in gene sequence, can mediate environmental effects on central and peripheral function. Epigenetic alterations including DNA methylation changes, histone modifications, and differential expression of non-coding RNAs (microRNA [miRNA] and long non-coding RNA) have been associated with several diseases. The objective of this review is to elucidate the molecular factors in the pathophysiology of IBS with an emphasis on epigenetic mechanisms. Emerging evidence for epigenetic changes in IBS includes changes in DNA methylation in animal models of IBS and patients with IBS, and various miRNAs that have been associated with IBS and endophenotypes, such as increased visceral sensitivity and intestinal permeability. DNA methylation, in particular, is an emerging field in the realm of complex diseases and a promising mechanism which can provide important insights into IBS pathogenesis and identify potential targets for treatment.

Cell detachment rapidly induces changes in noncoding RNA expression in human mesenchymal stromal cells.

Aims: To identify differential expression of noncoding RNAs after trypsinization in human mesenchymal stromal cells (hMSCs), focusing on miRNAs, piRNAsand circRNAs. Methods: hMSCs from the bone marrow of three donors were collected for RNA extraction, either lysed directly in monolayer or trypsinized and lysed within 30min. Total RNA was isolated and sequenced for the evaluation of miRNA and piRNA expression or RNaseR treated and labeled for circRNA array hybridization. RT-qPCR was performed to evaluate the stability of candidate reference genes. Results & conclusions: Alterations in levels of several noncoding RNAs are rapidly induced after trypsinization of hMSCs, affecting critical pathways. This should be carefully considered for a proper experimental design.

Abstract 2786: Effects of tumor microenvironment on the efferocytic and phagocytic genes of human macrophages

Abstract Macrophages are the first line of defense in the cellular environment in response to any antigenic or foreign invasion. Since cancer cells express antigenic molecules and create a tumor microenvironment quite different from the normal cellular environment, macrophages will attack this cancer cells as foreign invaders. However, the cancer cells suppress the macrophage activity by secreting compounds unknown to the cancer, biologists even today and recruit these macrophages to their benefit as tumor associated macrophages or TAM. In this study, we were interested to find out the genes and proteins that are involved in this conversion of cancer-fighting macrophages to cancer friendly macrophages. We co-cultured the prostate cancer cells along with the human macrophages, then collected these tumor micro environment (TME) exposed human macrophages, and isolated RNA from these cells. We further analyzed these tumor associated macrophages (TAM’s) along with control macrophages RNA by Microarray analysis using Affymetrix platform for gene expression studies. Our Phagocytosis results showed decreased phagocytic index in the tumor medium exposed macrophage cells as evidenced by the much lower relative fluorescence unit (RFU) recorded by the fluorometer in comparison to macrophages grown in absence of tumor medium. Further analysis of the gene expression studies by PARTEK coupled with Ingenuity Pathway Analysis (IPA®) showed down-regulation of several genes helping in the phagocytosis process and differential expression of several noncoding RNAs that control the expression of such phagocytic genes. The following oncomiR’s, miR 148,615,515,130,139 were -upregulated and tumor suppressor miR’s3130, let7c,101,103,383 were downregulated. The TARGET SCAN Software results showed these differential expression of noncoding RNA’s causing down regulation of phagocytosis promoting genes elf5A, Meg3, Tubb5, Sparcl-1, Uch-1, Bsg (CD147), Ube2v, and Pamr1. There is an up-regulation of RAP1GAP gene that causes downregulation of the tubulin genes that promote cytoskeletal assembly in forming phagosomes. Ingenuity Software analysis of the gene expression data also showed upregulation of anti-phagocytic genes IL10, CD16.IL18 and MMP9. IPA core canonical pathways analysis revealed the pathophysiology of complex cellular signaling, by which, the rogue cancer cells tame their enemies, the macrophages and actually make them their helper cells to survive and propagate in the tumor microenvironment and thus prepare for epithelial mesenchymal transition for future metastasis and cancer stem cell formation and progression. Further work is underway in our laboratory to decipher the complete biology of TAM formation. Acknowledgement: Supported by ECSU-NIH-MARC2T34GM100831-06, ECSU-NSF-LSAMP, and 5G12MD007597-25(NIMHD) Citation Format: Hirendra N. Banerjee, Kayla Johnston, Christopher Krauss, Santanu Dasgupta, Somiranjan Ghosh, Santosh Mandal. Effects of tumor microenvironment on the efferocytic and phagocytic genes of human macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2786.

Abstract 3583: Differential expression of noncoding RNAs in black compared with white laryngeal cancers

Abstract Background: Compared with other races, Blacks have maintained a higher incidence, prevalence, and poorer survival for laryngeal squamous cell carcinoma (LSCC). To date, a molecular basis remains undefined. Noncoding RNAs (ncRNAs), in particular microRNAs, have been found to be dysregulated in cancers with disparate outcomes. Ultraconserved RNAs (UCR), a highly conserved, new class of ncRNA, are regulated by miRNAs and differentially expressed in cancer. No studies to date have explored the dysregulation of these elements in Black compared with White LSCC. We present, here, our miRNA and UCR data from Black LSCC, White LSCC, and normal mucosal tissues. Methods: RNA was isolated from 32 fresh frozen tumors (16 Black and 16 White) and normal mucosal tissues (10 White and 1 Black). For miRNA analysis, small RNA library construction and sequencing were performed. Differentially expressed miRNAs identified through sequencing were considered for qPCR validation using the criteria of FDR &amp;lt;0.05, FC &amp;gt;1.5. The expression of 481 transcribed-UCRs (T-UCR) was profiled using primers designed to each T-UCRs. A T-UCR was considered expressed in a particular sample if the mean CT ≤ 35. miRNAs and T-UCR were considered differentially expressed if the fold change between the comparative groups was greater than 1.5-fold and p &amp;lt; 0.05 (FDR). Results: Our data show that there are significant differences in the somatic expression of two miRNAs, miR-9-5p and miR-191-5p, where both miRNAs were decreased in Black LSCC compared with White. However, when compared to normal mucosa, miR-9-5p was significantly overexpressed only in White LSCCs not in Black. In contrast, miR-191-5p was significantly decreased in Black LSCC compared to normal mucosa but not in White. This trend was seen also in our T-UCR data, where compared to normal mucosa, uc.424 was significantly overexpressed only in Black LSCC whereas uc.401 and uc.012 were significantly overexpressed only in White LSCC. Overall comparison of tumor to normal mucosa revealed 4 T-UCRs, uc.401, uc.389, uc.382, uc.218 were overexpressed in tumor compared to normal. No differences in T-UCR expression was identified in Black LSCC compared to White LSCC. Conclusions: In summary, our data show that there are somatic expression differences and baseline expression differences in ncRNAs between Black and White LSCC. Our data suggest that gene regulatory mechanisms may differ in Black and White LSCC. Additionally, we are the first to identify T-UCR expression differences in laryngeal cancer. Through their interplay with miRNAs, these elements may contribute to LSCC tumorigenesis. Future studies will focus on uncovering the functional consequences of our differentially expressed ncRNAs and determining the manner in which they impact disparate outcomes seen in LSCC. Citation Format: Kristianna Fredenburg, Jinmai Jiang, Tom Schmittgen. Differential expression of noncoding RNAs in black compared with white laryngeal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3583.

High-throughput sequencing reveals circular RNA hsa_circ_0000592 as a novel player in the carcinogenesis of gastric carcinoma.

Background/Aim: Gastric cancer is one of the most common malignant tumors, and its complex pathogenesis has not been fully elucidated. Circular RNAs (circRNAs) are involved in various biological processes and human diseases. However, their exact functional roles and mechanisms of action remain largely unclear. We previously discovered the differential expression of non-coding RNAs (ncRNAs) during the malignant transformation of human gastric epithelial cells. In this study, we investigated the functional roles of a significantly up-regulated circRNA (hsa_circ_0000592) in gastric cancer. Methods: N-methyl-N′-nitro-N-nitrosoguanidine (MNNG)-induced malignant-transformed gastric epithelial cells (GES-1-T) and normal gastric epithelial cells (GES-1-N) were analyzed by high-throughput circRNA sequencing. The top 15 up-regulated circRNAs in high-throughput sequencing results were further confirmed by qRT-PCR in different gastric epithelial cell lines. The function of the most significant circRNA (hsa_circ_0000592) was investigated by using RNA interference (RNAi) assays, fluorescence in situ hybridization analysis (FISH), and bioinformatics prediction methods. Results: A total of 1509 genes were up-regulated and 3142 genes were down-regulated in GES-1-T cells when compared with GES-1-N cells. When compared with GES-1-N cells, hsa_circ_0000592 was obviously up-regulated in GES-1-T cells, as well as in other gastric cancer cell lines. The silencing of hsa_circ_0000592 mRNA led to a decrease in cell proliferation, cell cycle arrest at the G0/G1 phase, an increased rate of apoptosis, and a reduction in cell migration. Furthermore, FISH showed that hsa_circ_0000592 was mainly located in the cytoplasm, and a bioinformatics analysis suggested that hsa_circ_0000592 might function by sponging multiple miRNAs, and most notably four conserved miRNAs, including miR-139-3p, miR-200, miR-367-3p, and miR-33a-3p. Conclusion: This study is the first to identify hsa_circ_0000592 as a novel circRNA with a critical role in MNNG-induced gastric cancer. Due to the essential role of hsa_circ_0000592 in gastric carcinoma cells, it may be considered as a potential biomarker for use in diagnosing gastric carcinoma. Our findings provide a new insight into the function of circRNAs in environmental carcinogen-induced gastric cancer.

Obesity-Related Epigenetic Changes After Bariatric Surgery.

Objective: In recent years, an increasing number of studies have begun focusing on epigenetics as a link between environmental factors and a greater predisposition to the development of obesity and its comorbidities. An important challenge in this field is the evaluation of the possibility of the reversal of obesity-related epigenetic marks by means of therapy to induce weight loss and if the beneficial effects of therapy in reducing obesity are mediated by epigenetic mechanisms. We aimed to offer an outline of the current results regarding to the impact of bariatric surgery on epigenetic regulation, as well as to show if the beneficial effect of this intervention could be mediated by epigenetic mechanisms.Methods: A review of the scientific publications in PubMed was performed by using key words related to obesity, epigenetics and bariatric surgery to provide an update of recent findings in this area of research. The most relevant and recently published articles and abstracts were selected to frame this review.Results: Previous studies have demonstrated the presence of differential DNA methylation after bariatric surgery and the differential expression of non-coding RNAs. Therefore, epigenetic regulation could mediate the benefit of bariatric surgery on body weight and the metabolic disturbances associated with excess body weight, such as insulin resistance, hypertension, and cardiovascular disease. This evidence is relatively new as epigenetic regulation was first evaluated in the obesity field only a few years ago. However, there is an urgent need to perform longitudinal studies to evaluate the capacity of epigenetic marks in the prediction of bariatric surgery response.Conclusions: Bariatric surgery appears to be capable of partially reversing the obesity-related epigenome. The identification of potential epigenetic biomarkers predictive for the success of bariatric surgery may open new doors to personalized therapy for severe obesity.

Transgenerational Response to Heat Stress in the Form of Differential Expression of Noncoding RNA Fragments in Brassica rapa Plants.

Epigenetic regulations in the form of changes in differential expression of noncoding RNAs (ncRNAs) are an essential mechanism of stress response in plants. Previously we showed that heat treatment in L. results in the differential processing and accumulation of ncRNA fragments (ncRFs) stemming from transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), and small nucleolar RNAs (snoRNAs). In this work, we analyzed whether ncRFs are differentially expressed in the progeny of heat-stressed plants. We found significant changes in the size of tRF reads and a significant decrease in the percentage of tRFs mapping to tRNA-Ala, tRNA-Arg, and tRNA-Tyr and an increase in tRFs mapping to tRNA-Asp. The enrichment analysis showed significant differences in processing of tRFs from tRNA, tRNA, tRNA, tRNA, tRNA, and tRNA isoacceptors. Analysis of potential targets of tRFs showed that they regulate brassinosteroid metabolism, the proton pump ATPase activity, the antiporter activity, the mRNA decay activity as well as nucleosome positioning and the epigenetic regulation of transgenerational response. Gene ontology term analysis of potential targets demonstrated a significant enrichment in tRFs that potentially targeted a cellular component endoplasmic reticulum (ER) and in small nucleolar RNA fragments (snoRFs), the molecular function protein binding. To summarize, our work demonstrated that the progeny of heat-stressed plants exhibit changes in the expression of tRFs and snoRFs but not of small nuclear RNA fragments (snRFs) or ribosomal RNA fragments (rRFs) and these changes likely better prepare the progeny of stressed plants to future stress encounters.

Correlation Analyses Reveal a Limited Role of Transcription in Genome-Wide Differential MicroRNA Expression in Mammals.

Transcription initiates the cascade of gene expression and is often assumed to play a predominant role in determining how much gene products are ultimately expressed. The relationship between mRNA levels and protein levels has been studied extensively to reveal the degrees of transcriptional and post-transcriptional regulation of protein expression. The extent to which transcription globally controls the differential expression of non-coding RNAs, however, is poorly defined. MicroRNAs (miRNAs) are a class of small, non-coding RNAs whose biogenesis involves transcription followed by extensive processing. Here, using hundreds of datasets produced from the ENCODE (Encyclopedia of DNA Elements) project we calculated the correlations between transcriptional activity and mature miRNA expression in diverse human cells, human tissues, and mouse tissues. While correlations vary among samples, most correlation coefficients are small. Interestingly, excluding miRNAs that were discovered later or weighting miRNA expression improves the correlations. Our results suggest that transcription contributes only modestly to differential miRNA expression at the genome-wide scale in mammals.

High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer.

Abstract SY05-01: microRNAs: Micromanagers of human cancers

Abstract The newly discovered differential expression in numerous tissues, key cellular processes and multiple diseases for several families of long and short non-codingRNAs (ncRNAs, RNAs that do not codify for proteins but for RNAs with regulatory functions), including the already famous class of microRNAs (miRNAs) strongly suggest that the scientific and medical communities have significantly underestimated the spectrum of ncRNAs whose altered expression has significant consequences in diseases. MicroRNA and other short or long non-codingRNAs alterations are involved in the initiation, progression and metastases of human cancer. The main molecular alterations are represented by variations in gene expression, usually mild and with consequences for a vast number of target protein coding genes. The causes of the widespread differential expression of non-codingRNAs in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the processing machinery. MicroRNA and other short or long non-codingRNAs expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify non-codingRNAs that may represent downstream targets of activated oncogenic pathways or that are targeting protein coding genes involved in cancer. Recent studies proved that miRNAs and non-coding ultraconserved genes are main candidates for the elusive class of cancer predisposing genes and that other types of non-codingRNAs participate in the genetic puzzle giving rise to the malignant phenotype. Last, but not least, the shown expression correlations of these new ncRNAs with cancer metastatic potential and overall survival rates suggest that at least some member of these novel classes of molecules could potentially find use as biomarkers or novel therapeutics in cancers and other diseases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY05-01. doi:1538-7445.AM2012-SY05-01

Abstract SY13-01: Noncoding RNAs: From bench to bedside

Abstract The newly discovered differential expression in numerous tissues, key cellular processes and multiple diseases for several families of long and short noncoding RNAs (ncRNAs, genes that do not codify for proteins but for RNAs with regulatory functions), including the already famous class of microRNAs (miRNAs) strongly suggest that the scientific and medical communities have significantly underestimated the spectrum of ncRNAs whose altered expression has significant consequences in diseases. MicroRNA and other short or long noncoding RNAs alterations are involved in the initiation, progression and metastases of human cancer. The main molecular alterations are represented by variations in gene expression, usually mild and with consequences for a vast number of target protein coding genes. The causes of the widespread differential expression of noncoding RNAs in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the processing machinery. MicroRNA and other short or long noncoding RNAs expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify noncoding RNAs that may represent downstream targets of activated oncogenic pathways or that are targeting protein coding genes involved in cancer. Recent studies proved that miRNAs and non-coding ultraconserved genes are main candidates for the elusive class of cancer predisposing genes and that other types of noncoding RNAs participate in the genetic puzzle giving rise to the malignant phenotype. Last, but not least, the shown expression correlations of these new ncRNAs with cancer metastatic potential and overall survival rates suggest that at least some member of these novel classes of molecules could potentially find use as biomarkers or novel therapeutics in cancers and other diseases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY13-01. doi:10.1158/1538-7445.AM2011-SY13-01

Differential expression of non-coding RNAs and continuous evolution of the X chromosome in testicular transcriptome of two mouse species.

BackgroundTight regulation of testicular gene expression is a prerequisite for male reproductive success, while differentiation of gene activity in spermatogenesis is important during speciation. Thus, comparison of testicular transcriptomes between closely related species can reveal unique regulatory patterns and shed light on evolutionary constraints separating the species.Methodology/Principal FindingsHere, we compared testicular transcriptomes of two closely related mouse species, Mus musculus and Mus spretus, which diverged more than one million years ago. We analyzed testicular expression using tiling arrays overlapping Chromosomes 2, X, Y and mitochondrial genome. An excess of differentially regulated non-coding RNAs was found on Chromosome 2 including the intronic antisense RNAs, intergenic RNAs and premature forms of Piwi-interacting RNAs (piRNAs). Moreover, striking difference was found in the expression of X-linked G6pdx gene, the parental gene of the autosomal retrogene G6pd2.Conclusions/SignificanceThe prevalence of non-coding RNAs among differentially expressed transcripts indicates their role in species-specific regulation of spermatogenesis. The postmeiotic expression of G6pdx in Mus spretus points towards the continuous evolution of X-chromosome silencing and provides an example of expression change accompanying the out-of-the X-chromosomal retroposition.