Micronutrients for Improved Management of Huntington’s Disease
Kedar N. Prasad in 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.
Small noncoding RNAs as biomarkers for pregnancy complications
Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos in New Technologies and Perinatal Medicine, 2019
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).
Epigenetic and Assisted Reproduction Experimental Studies
Cristina Camprubí, Joan Blanco in Epigenetics and Assisted Reproduction, 2018
The synthesis of miRNAs starts in the nucleus with the transcription of RNA hairpins, named primary miRNAs (pri-miRNAs). This transcription is generally performed by polymerase II (16). The miRNA coding regions are generally isolated and widespread along the whole genome, although some of them are clustered together. These clusters are transcribed as single long precursors and then processed into individual miRNAs (17). The hairpin structures are cleaved by the microprocessor complex, which comprises an RNase III-type nuclease (DROSHA) and DiGeorge Syndrome Critical Region 8 (DGCR8). The generated intermediate precursors (pre-miRNAs) are transported to the cytoplasm through nuclear pores by Exportin-5. The RNase III endonuclease, DICER, processes these precursors and creates ∼22 base pairs duplex (miRNA:miRNA*). Afterward, the functionally mature monocatenary miRNAs are originated (14). In most cases, only one strand of the miRNA:miRNA* duplex remains functional while the other one is degraded (the miRNA* strand). Nevertheless, in some cases both of them can become functional (18). For example, it has been discovered that both strands remain functional in most miRNA duplex precursors of certain tissues, including testis (19). Mature miRNA molecules are attached to Argonaute (Ago) and TNRC6 (trinucleotide repeat-containing 6) proteins, forming the ribonucleoprotein miRNA-induced silencing complex (miRISC) (20) (Figure 9.2).
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).
Emerging roles of noncoding RNAs in T cell differentiation and functions in autoimmune diseases
Published in International Reviews of Immunology, 2019
Additional, non-canonical pathway for the biogenesis of miRNAs was also reported in Caenorhabditis elegans, Drosophila melanogaster and mammals, which is Drosha-independent. In this pathway, short-hairpin introns are spliced out by spliceosome into “pre-miRNA” known as “mirtrons”. However, this is an uncommon pathway for miRNA biogenesis and majority of miRNA are generated by Drosha-dependent cleavage pathway [63, 64].
Biological and Immunological Aspects of Iron Deficiency Anemia in Cancer Development: A Narrative Review
Published in Nutrition and Cancer, 2018
Fatema Zohora, Katayoon Bidad, Zahra Pourpak, Mostafa Moin
MicroRNAs are small noncoding RNAs of about 22 nucleotides. They are the main regulators of gene expression by inducing translational repression and mRNA decay (67). They are likely an important factor in tumorigenesis and metastasis by regulating specific oncogenes, tumor suppressors, and cancer stem cells (68). MicroRNAs are critically important for the regulation of innate and adaptive immune system (69), proper inflammatory response (70), development, and differentiation of immune cells as well as myeloid-derived immune suppressor cells (71). MicroRNAs are involved in iron homeostasis by posttranscriptionally regulating genes associated with cellular iron uptake, storage, and utilization (72). Interestingly, iron is a key element for the activity of the two important proteins like as DiGeorge Syndrome Critical Region-8 (DGCR-8) protein (heme-binding protein and co-factor of Drosha) and Poly (rC)-binding protein 2(Pcbp2). Drosha is responsible for the processing of pri-microRNAs into pre-microRNAs within the nucleus (73). Pcbp2 enhances the cytosolic processing of pre-microRNAs into mature microRNAs (74). Therefore, abnormal heme biosynthesis and degradation may alter microRNA-mediated gene regulation networks. Moreover, the biogenesis and expression of microRNAs are greatly regulated by hypoxia (75) and ROS (76) which are very common features in iron deficiency. As an example, hypoxia-inducible-miR-210 promotes cell proliferation, Vascular Endothelial Growth Factor (VEGF) expression and cell survival in hypoxic regions within tumors. (76,77). Due to hypoxia, the over expression of MiR-210 and Mir-373 have been reported to downregulate the RAD 52 and RAD 23B genes respectively in an in-vitro study. These genes are responsible as for DNA repair systems (78). Another example is let-7 microRNA, which was demonstrated as tumor suppressor microRNA in several in vitro studies (79–82). The expression of let-7 was decreased by oxidative stress in an in vitro study with auditory cells. (83). The above findings suggest that iron is a key element in microRNAs and hypoxia and ROS caused by IDA can negatively affect gene regulation system of microRNAs resulting in increased cancer risk.
Related Knowledge Centers
- Argonaute
- Endoribonuclease
- Enzyme
- Eukaryote
- Ribosomal Rna
- Rna
- Ribonuclease III
- Gene
- Dicer
- Base Pair