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Role of Epigenetics in Immunity and Immune Response to Vaccination
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
miRNAs are transcribed by RNA polymerase II as a hairpin loop structure, called the pri-miRNA. Following transcription, pri-miRNAs are capped and polyadenilated (Cai, Hagedorn, and Cullen 2004). Pri-miRNAs undergo a nuclear processing where the pri-miRNA is cleaved by microprocessor complex, comprised of DiGeorge syndrome critical region 8 (DGCR8) and Drosha proteins (Gregoryi, Chendrimada, and Shiekhattar 2006; Conrad et al. 2014). The cleavage product is called a pre-miRNA. Nuclear processing is followed by the export of pre-miRNA to cytoplasm by Exportin. Pre-miRNA is cleaved by an enzyme called dicer to yield a double stranded miRNA complex. Following the cleavage by dicer, one strand of this miRNA duplex is loaded into the RNA-induced silencing complex (RISC) to interact with its target (Kim and Kim 2012; Park et al. 2011). Gene silencing by miRNAs has two modes depending on the miRNA target complementarity. Perfect or near perfect complementarity between the miRNA and its target mRNA induces the cleavage and degradation of target mRNA. In case of a non-perfect complementarity, the target mRNA is silenced through inhibition of translation (Lim et al. 2005).
Small noncoding RNAs as biomarkers for pregnancy complications
Published in Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos, New Technologies and Perinatal Medicine, 2019
Liron Yoffe, Meitar Grad, Avital Luba Polsky, Moshe Hod, Noam Shomron
miRNAs are an abundant class of small (∼22 nucleotides) ncRNAs that are estimated to downregulate the expression of more than 60% of protein-coding genes (6,9). miRNAs play pivotal post-transcriptional regulatory roles in various physiological functions. They bind messenger RNAs (mRNAs) at their 3′ untranslated region (UTR) and initiate either the mRNA degradation or translational repression (9,10). miRNAs are transcribed by RNA polymerase II from either specific miRNA gene loci or through splicing of mirtrons between exons of a host gene (6,9,11,12). Both transcription processes result in the formation of primary miRNAs (pri-miRNAs) that are processed by ribonuclease III (RNase III) enzymes Drosha and Dicer (along with other enzymes and aiding proteins) to form precursor miRNAs (pre-miRNAs) and then mature miRNAs (6,9,11,12). Mature miRNAs are then loaded into the RNA-induced silencing complex (RISC) to downregulate mRNA translation (6,9,11,12). A single miRNA can regulate tens to hundreds of downstream genes from a wide spectrum of biological pathways (13) and may also interact with other miRNAs to regulate gene expression (6). Thus, some miRNAs can be considered master regulators of various biological processes, such as cell proliferation, differentiation, apoptosis, and development (6,9).
Micronutrients for Improved Management of Huntington’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Transgenic HD mouse models (YAC128 and R6/2) and 3-nitropropionic acid (3-NP)-induced rat HD model revealed abnormal biogenesis of microRNAs that was age-dependent. For example, at 5 months, increased expression of nuclear Drosha that cleaves primary miR to form pre-miR was associated with enhanced expression of dominant miRs; whereas, at 12 months, decreased expression of Dicer that cleaves pre-miR to form mature miR was associated with reduced expression of miRs in YAC128 mice.54 In 10 week-old R6/2 mice, decreased expression of Drosha was associated with reduced expression of dominant miRs. Expressions of 9 miRs (miR-22, miR-29c, miR-128, miR-132, miR-138, miR-218, miR-222, miR-344, and miR-674) were downregulated in 12-month-old YAC128 and 10-week-old R6/2 mice. Similar dynamic changes in the profiles of miRs were observed in 3NP-treated rats.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
Small molecule inhibitors against miRNAs have generally targeted either the Drosha or the Dicer cleavage sites of the pri- or pre-miRNA, respectively. The first small molecule inhibitor targeting miR-21, an anti-apoptotic miRNA upregulated in several cancers, was identified by Gumireddy et al. by high throughput screening [50]. Herein, a primary screen of >1000 compounds identified diazobenzene as the most effective miR-21 inhibitor, which functioned by suppressing biogenesis of miR-21. Combinatorial screening systems that utilize a small molecule array to multiplex screen an RNA motif library for binding in a single experiment were used to identify a small molecule inhibitor of miR-96 (targaprimir-96) [51] that bound to the Drosha cleavage site, inhibiting processing and biogenesis of miR-96, preventing suppression of the proapoptotic factor forkhead box O1 (FOXO1). Further small molecule inhibitors of miRNAs targeting either Drosha or Dicer cleavage have been identified for miR-210 [52], miR-544 [53], and miR-122 [54] among numerous others.
The Drosha rs10719 T>C polymorphism is associated with preeclampsia susceptibility
Published in Clinical and Experimental Hypertension, 2018
Mahnaz Rezaei, Fatemeh Eskandari, Abbas Mohammadpour-Gharehbagh, Batool Teimoori, Minoo Yaghmaei, Mojgan Mokhtari, Saeedeh Salimi
These miRNAs are synthesized as a long RNA transcript called as a pri-miRNA. The pri-miRNA cleaved by the Drosha enzyme (nucleus enzyme) and produces a 70-bp stem-loop structure, which is named the pre-miRNA. The Drosha belongs to a protein complex, which also contains the Pasha protein. The presence of this protein is necessary for Drosha activity. Then, the pre-miRNA is further processed by an RNase enzyme called Dicer into mature miRNAs in the cell cytoplasm. Therefore, the Drosha is a key enzyme in miRNA processing machinery, where any defect in its function or concentration could affect the miRNA processing and concentration (10,11). Evidence shows altered levels of Drosha expressions and/or genetic variations in different disease (15,34). There are several genetic variants in the Drosha gene; therefore, in the current study we evaluated the possible effects of rs10719 polymorphism in the 3′–UTR region and rs6877842 polymorphism in the promoter region of the Drosha gene on PE predisposition. Since these polymorphisms are located in the 3′–UTR and promoter regions of Drosha gene, they may affect the structure and function of the produced transcript of Drosha gene as well as the expression level and subsequently miRNAs processing (16).
Desmoplastic small round cell tumor: from state of the art to future clinical prospects
Published in Expert Review of Anticancer Therapy, 2023
Shushan Hovsepyan, Claudia Giani, Sandro Pasquali, Angela Di Giannatale, Stefano Chiaravalli, Chiara Colombo, Daniel Orbach, Luca Bergamaschi, Sabina Vennarini, Susanne Andrea Gatz, Patrizia Gasparini, Pablo Berlanga, Michela Casanova, Andrea Ferrari
MicroRNAs (miRNAs) are short RNA molecules that regulate the post-transcriptional silencing of target genes. They have been investigated as biomarkers in liquid biopsy because miRNA profiles may distinguish between normal and cancerous tissue, reflect tumor expression in the serum of cancer patients, and predict outcomes or responses to therapy [48,49]. EWS reportedly regulates DROSHA expression, and modulates miRNA biogenesis, pointing to an alteration of miRNA regulatory mechanisms mediated by this protein [50].