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Psychiatry Research Nov 2021Schizophrenia (SCZ) is a chronic psychotic disorder that contributes significantly to disability, affecting behavior, thought, and cognition. It has long been known that... (Review)
Review
Schizophrenia (SCZ) is a chronic psychotic disorder that contributes significantly to disability, affecting behavior, thought, and cognition. It has long been known that there is a heritable component to schizophrenia; studies in both the pre-genomic and post-genomic era, however, have failed to elucidate fully the genetic basis for this complex disease. Epigenetic processes - broadly, those which contribute to changes in gene expression without altering the genetic code itself - may help to understand better the mechanisms leading to development of SCZ. The objective of this review is to synthesize current knowledge of the epigenetic mechanisms involved in schizophrenia. Specifically, DNA methylation studies in both peripheral and post-mortem brain samples in SCZ are reviewed, as are epigenetic mechanisms including histone modification. The promising role of non-coding RNA including micro-RNA (miRNA) and its role as a potential diagnostic and therapeutic biomarker is outlined, as are epigenetic age acceleration and telomere shortening. Finally, we discuss limitations in current knowledge and propose future research directions.
Topics: DNA Methylation; Epigenesis, Genetic; Humans; MicroRNAs; Psychotic Disorders; Schizophrenia
PubMed: 34638051
DOI: 10.1016/j.psychres.2021.114218 -
BioTechniques Oct 2019Several approaches for miRNA expression analysis have been developed in recent years. In this article, we provide an updated and comprehensive review of available... (Review)
Review
Several approaches for miRNA expression analysis have been developed in recent years. In this article, we provide an updated and comprehensive review of available qPCR-based methods for miRNA expression analysis and discuss their advantages and disadvantages. Existing techniques involve the use of stem-loop reverse transcriptase-PCR, polyadenylation of RNAs, ligation of adapters or RT with complex primers, using universal or miRNA-specific qPCR primers and/or probes. Many of these methods are oriented towards the expression analysis of mature miRNAs and few are designed for the study of pre-miRNAs and pri-miRNAs. We also discuss findings from articles that compare results from existing methods. Finally, we suggest key points for the improvement of available techniques and for the future development of additional methods.
Topics: Computer Simulation; DNA Primers; Gene Expression; High-Throughput Nucleotide Sequencing; MicroRNAs; Polyadenylation; Real-Time Polymerase Chain Reaction; Software
PubMed: 31560239
DOI: 10.2144/btn-2019-0065 -
Circulation Research Mar 2023Platelets can infiltrate ischemic myocardium and are increasingly recognized as critical regulators of inflammatory processes during myocardial ischemia and reperfusion...
BACKGROUND
Platelets can infiltrate ischemic myocardium and are increasingly recognized as critical regulators of inflammatory processes during myocardial ischemia and reperfusion (I/R). Platelets contain a broad repertoire of microRNAs (miRNAs), which, under certain conditions such as myocardial ischemia, may be transferred to surrounding cells or released into the microenvironment. Recent studies could demonstrate that platelets contribute substantially to the circulating miRNA pool holding the potential for so far undiscovered regulatory functions. The present study aimed to determine the role of platelet-derived miRNAs in myocardial injury and repair following myocardial I/R.
METHODS
In vivo model of myocardial I/R, multimodal in vivo and ex vivo imaging approaches (light-sheet fluorescence microscopy, positron emission tomography and magnetic resonance imaging, speckle-tracking echocardiography) of myocardial inflammation and remodeling, and next-generation deep sequencing analysis of platelet miRNA expression.
RESULTS
In mice with a megakaryocyte/platelet-specific knockout of pre-miRNA processing ribonuclease , the present study discloses a key role of platelet-derived miRNAs in the tightly regulated cellular processes orchestrating left ventricular remodeling after myocardial I/R following transient left coronary artery ligation. Disruption of the miRNA processing machinery in platelets by deletion of resulted in increased myocardial inflammation, impaired angiogenesis, and accelerated development of cardiac fibrosis, culminating in an increased infarct size by d7 that persisted through d28 of myocardial I/R. Worsened cardiac remodeling after myocardial infarction in mice with a platelet-specific deletion resulted in an increased fibrotic scar formation and distinguishably increased perfusion defect of the apical and anterolateral wall at day 28 post-myocardial infarction. Altogether, these observations culminated in an impaired left ventricular function and hampered long-term cardiac recovery after experimental myocardial infarction and reperfusion therapy. Treatment with the P2Y (P2Y purinoceptor 12) antagonist ticagrelor completely reversed increased myocardial damage and adverse cardiac remodeling observed in mice.
CONCLUSIONS
The present study discloses a critical role of platelet-derived miRNA in myocardial inflammation and structural remodeling processes following myocardial I/R.
Topics: Mice; Animals; Blood Platelets; MicroRNAs; Ventricular Remodeling; Myocardial Reperfusion Injury; Myocardial Ischemia; Myocardial Infarction; Coronary Artery Disease; Inflammation; Disease Models, Animal
PubMed: 36891903
DOI: 10.1161/CIRCRESAHA.122.322459 -
Biochimica Et Biophysica Acta. Reviews... Jan 2021Recent advances have begun to clarify the physiological and pathological roles of non-coding RNAs (ncRNAs) in various diseases, including cancer. Among these, microRNAs... (Review)
Review
Recent advances have begun to clarify the physiological and pathological roles of non-coding RNAs (ncRNAs) in various diseases, including cancer. Among these, microRNAs (miRNAs) have been the most studied and have emerged as key players that are involved in the regulation of important growth regulatory pathways in cancer pathogenesis. The ability of a single ncRNA to modulate the expression of multiple downstream gene targets and associated pathways, have provided a rationale to pursue them for therapeutic drug development in cancer. In this context, early data from pre-clinical studies have demonstrated that synthetic miRNA-based therapeutic molecules, along with various protective coating approaches, has allowed for their efficient delivery and anti-tumor activity. In fact, some of the miRNA-based cancer therapeutic strategies have shown promising results even in early-phase human clinical trials. While the enthusiasm for ncRNA-based cancer therapeutics continue to evolve, the field is still in the midst of unraveling a more precise understanding of the molecular mechanisms and specific downstream therapeutic targets of other lesser studied ncRNAs such as the long-non-coding RNAs, transfer RNAs, circular RNAs, small nucleolar RNAs, and piwi-interacting RNAs. This review article provides the current state of knowledge and the evolving principles for ncRNA-based therapeutic approaches in cancer, and specifically highlights the importance of data to date and the approaches that are being developed to overcome the challenges associated with their delivery and mitigating the off-target effects in human cancers.
Topics: Humans; MicroRNAs; Molecular Targeted Therapy; Neoplasms; RNA, Circular; RNA, Long Noncoding; RNA, Small Interfering; RNA, Untranslated
PubMed: 33316377
DOI: 10.1016/j.bbcan.2020.188491 -
Nature Mar 2023RNA silencing relies on specific and efficient processing of double-stranded RNA by Dicer, which yields microRNAs (miRNAs) and small interfering RNAs (siRNAs). However,...
RNA silencing relies on specific and efficient processing of double-stranded RNA by Dicer, which yields microRNAs (miRNAs) and small interfering RNAs (siRNAs). However, our current knowledge of the specificity of Dicer is limited to the secondary structures of its substrates: a double-stranded RNA of approximately 22 base pairs with a 2-nucleotide 3' overhang and a terminal loop. Here we found evidence pointing to an additional sequence-dependent determinant beyond these structural properties. To systematically interrogate the features of precursor miRNAs (pre-miRNAs), we carried out massively parallel assays with pre-miRNA variants and human DICER (also known as DICER1). Our analyses revealed a deeply conserved cis-acting element, termed the 'GYM motif' (paired G, paired pyrimidine and mismatched C or A), near the cleavage site. The GYM motif promotes processing at a specific position and can override the previously identified 'ruler'-like counting mechanisms from the 5' and 3' ends of pre-miRNA. Consistently, integrating this motif into short hairpin RNA or Dicer-substrate siRNA potentiates RNA interference. Furthermore, we find that the C-terminal double-stranded RNA-binding domain (dsRBD) of DICER recognizes the GYM motif. Alterations in the dsRBD reduce processing and change cleavage sites in a motif-dependent fashion, affecting the miRNA repertoire in cells. In particular, the cancer-associated R1855L substitution in the dsRBD strongly impairs GYM motif recognition. This study uncovers an ancient principle of substrate recognition by metazoan Dicer and implicates its potential in the design of RNA therapeutics.
Topics: Humans; Base Pairing; DEAD-box RNA Helicases; MicroRNAs; Ribonuclease III; RNA Interference; RNA, Double-Stranded; RNA, Small Interfering; RNA Precursors; Base Sequence; Nucleic Acid Conformation
PubMed: 36813957
DOI: 10.1038/s41586-023-05722-4 -
International Journal of Molecular... May 2022TRUE gene silencing is an RNA-mediated gene expression control technology and is termed after tRNase Z-utilizing efficacious gene silencing. In this review, I overview... (Review)
Review
TRUE gene silencing is an RNA-mediated gene expression control technology and is termed after tRNase Z-utilizing efficacious gene silencing. In this review, I overview the potentiality of small guide RNA (sgRNA) for TRUE gene silencing as novel therapeutics. First, I describe the physiology of tRNase Z and cellular small RNA, and then sgRNA and TRUE gene silencing. An endoribonuclease, tRNase Z, which can efficiently remove a 3' trailer from pre-tRNA, is thought to play the role in tRNA maturation in the nucleus and mitochondria. There exist various small RNAs including miRNA and fragments from tRNA and rRNA, which can function as sgRNA, in living cells, and human cells appear to be harnessing cytosolic tRNase Z for gene regulation together with these small RNAs. By utilizing the property of tRNase Z to recognize and cleave micro-pre-tRNA, a pre-tRNA-like or micro-pre-tRNA-like complex, as well as pre-tRNA, tRNase Z can be made to cleave any target RNA at any desired site under the direction of an artificial sgRNA that binds a target RNA and forms the pre-tRNA-like or micro-pre-tRNA-like complex. This general RNA cleavage method underlies TRUE gene silencing. Various examples of the application of TRUE gene silencing are reviewed including the application to several human cancer cells in order to induce apoptosis. Lastly, I discuss the potentiality of sgRNA as novel therapeutics for multiple myeloma.
Topics: Endoribonucleases; Gene Silencing; Humans; MicroRNAs; RNA Precursors; RNA, Transfer; RNA, Guide, CRISPR-Cas Systems
PubMed: 35628198
DOI: 10.3390/ijms23105387 -
International Journal of Molecular... Dec 2022MicroRNAs (miRNAs) act as master regulators of gene expression in homeostasis and disease. Despite the rapidly growing body of evidence on the theranostic potential of... (Review)
Review
MicroRNAs (miRNAs) act as master regulators of gene expression in homeostasis and disease. Despite the rapidly growing body of evidence on the theranostic potential of restoring miRNA levels in pre-clinical models, the translation into clinics remains limited. Here, we review the current knowledge of miRNAs as T-cell targeting immunotherapeutic tools, and we offer an overview of the recent advances in miRNA delivery strategies, clinical trials and future perspectives in RNA interference technologies.
Topics: MicroRNAs; T-Lymphocytes; RNA Interference; Precision Medicine; Immunotherapy
PubMed: 36613706
DOI: 10.3390/ijms24010250 -
Methods in Molecular Biology (Clifton,... 2022MicroRNA (miRNA) studies have been one of the most popular research areas in recent years. Although thousands of miRNAs have been detected in several species, the... (Review)
Review
MicroRNA (miRNA) studies have been one of the most popular research areas in recent years. Although thousands of miRNAs have been detected in several species, the majority remains unidentified. Thus, finding novel miRNAs is a vital element for investigating miRNA mediated posttranscriptional gene regulation machineries. Furthermore, experimental methods have challenging inadequacies in their capability to detect rare miRNAs, and are also limited to the state of the organism under examination (e.g., tissue type, developmental stage, stress-disease conditions). These issues have initiated the creation of high-level computational methodologies endeavoring to distinguish potential miRNAs in silico. On the other hand, most of these tools suffer from high numbers of false positives and/or false negatives and as a result they do not provide enough confidence for validating all their predictions experimentally. In this chapter, computational difficulties in detection of pre-miRNAs are discussed and a machine learning based approach that has been designed to address these issues is reviewed.
Topics: Computational Biology; Machine Learning; MicroRNAs
PubMed: 34432278
DOI: 10.1007/978-1-0716-1170-8_8 -
Recent Results in Cancer Research.... 2020Deregulation of microRNA expression has been shown to play an important role in human malignancies. The identification of circulating-free miRNAs in biofluids a decade... (Review)
Review
Deregulation of microRNA expression has been shown to play an important role in human malignancies. The identification of circulating-free miRNAs in biofluids a decade ago led to great enthusiasm and motivation to develop non-invasive tests based on the expression of these small non-coding RNAs. Herein, we review the progress within the field of research for identifying circulating miRNA cancer biomarkers and discuss the advantages and challenges associated with this. We also discuss the methodological and analytical variables, which may influence the final miRNA quantification and the importance of standardizing pre-analytical, analytical, and post-analytical processes in order to enable a successful translation of the results from basic research into the clinics.
Topics: Biomarkers, Tumor; Humans; MicroRNAs; Neoplasms
PubMed: 31605235
DOI: 10.1007/978-3-030-26439-0_15 -
Essays in Biochemistry Dec 2020microRNAs (miRNAs) play essential roles in mouse embryonic stem cells (ESCs) and early embryo development. The exact mechanism by which miRNAs regulate cell fate... (Review)
Review
microRNAs (miRNAs) play essential roles in mouse embryonic stem cells (ESCs) and early embryo development. The exact mechanism by which miRNAs regulate cell fate transition during embryo development is still not clear. Recent studies have identified and captured various pluripotent stem cells (PSCs) that share similar characteristics with cells from different stages of pre- and post-implantation embryos. These PSCs provide valuable models to understand miRNA functions in early mammalian development. In this short review, we will summarize recent work towards understanding the function and mechanism of miRNAs in regulating the transition or conversion between different pluripotent states. In addition, we will highlight unresolved questions and key future directions related to miRNAs in pluripotent state transition. Studies in these areas will further our understanding of miRNA functions in early embryo development, and may lead to practical means to control human PSCs for clinical applications in regenerative medicine.
Topics: Animals; Cell Differentiation; Embryonic Development; Gene Expression; Gene Expression Regulation, Developmental; Humans; Mice; MicroRNAs; Mouse Embryonic Stem Cells
PubMed: 33034348
DOI: 10.1042/EBC20200028