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RNA-seq Analysis
Published in Altuna Akalin, Computational Genomics with R, 2020
RNA-seq generates valuable data that contains information not only at the gene level but also at the level of exons and transcripts. Moreover, the kind of information that we can extract from RNA-seq is not limited to expression quantification. It is possible to detect alternative splicing events such as novel isoforms (Trapnell et al., 2010), and differential usage of exons (Anders et al., 2012). It is also possible to observe sequence variants (substitutions, insertions, deletions, RNA-editing) that may change the translated protein product (McKenna et al., 2010). In the context of cancer genomes, gene-fusion events can be detected with RNA-seq (McPherson et al., 2011). Finally, for the purposes of gene prediction or improving existing gene predictions, RNA-seq is a valuable method (Stanke and Morgenstern, 2005). In order to learn more about how to implement these, it is recommended that you go through the tutorials of the cited tools.
Molecular and Cellular Pathogenesis of Systemic Lupus Erythematosus
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
George C. Tsokos, Yuang-Taung Juang, Christos G. Tsokos, Madhusoodana P. Nambiar
Although the precise molecular mechanisms underlying ζ chain deficiency is still being examined, current evidence supports the possibility of a transcriptional defect. In SLE, T cells that expressed low levels of T cell receptor ζ chain transcripts, cloning and sequencing revealed more frequent heterogeneous polymorphisms/ mutations and alternative splicing of T cell receptor ζ chain.12,23,24 Most of these mutations are localized to the three immunoreceptor tyrosine activation motifs (ITAM) or guanosine triphosphate (GTP) binding domain and could functionally affect the ζ chain providing a molecular basis to the known T cell signaling abnormalities in SLE T cells. Absence of the mutations/ polymorphisms in the genomic DNA suggests that these are the consequence of irregular RNA editing. SLE patients also showed significant increase in the splice variation of the ζ chain. The splicing abnormality included two insertion splice variants of 145 bases and 93 bases between exons I and II, and also several deletion splice variants of T cell recceptor ζ chain resulting from the deletion of individual exons II, VI, VII, or a combined deletion of exons V and VI; VI and VII; II, III and IV; and V, VI and VII in SLE T cells.
Advancements in ocular gene therapy delivery: vectors and subretinal, intravitreal, and suprachoroidal techniques
Published in Expert Opinion on Biological Therapy, 2022
Kyle D Kovacs, Thomas A Ciulla, Szilárd Kiss
RNA modulation targets the transcription, processing, or translation of mRNA. One highly mutation-specific approach is the development of non-coding RNA that regulates mRNA expression. Antisense oligonucleotides (ASOs) modulate the expression of mRNA via complimentary binding in the cell nucleus. Currently, ProQR (Leiden, the Netherlands) is actively developing ASOs for CEP290-related LCA, ABCA4-related retinal degeneration, and RHO-associated RP. Sepofarsen (QR-110) is an intravitreally delivered ASO for the treatment of the c.2991+1655A>G variant of CEP290-associated LCA, which showed promise in Phase I/IIa trials that was not corroborated in Phase II/III trials [51–53]. A similar concept to ASOs is the use of small interfering RNA (siRNA) that are double-stranded RNA that alter mRNA expression in cell cytoplasm. Of course, there are numerous approaches to RNA editing that pose the potential for application to gene therapy; however, many of these approaches are still preclinical or purely theoretical [54].
Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?
Published in Expert Opinion on Orphan Drugs, 2021
Ruofan Connie Han, Lewis E. Fry, Ariel Kantor, Michelle E. McClements, Kanmin Xue, Robert E. MacLaren
Finally, CRISPR-directed RNA editing represents another novel approach to targeted correction of single nucleotide variants, in RNA rather than DNA [54]. A wide variety of approaches have been developed to edit RNA in vitro. Each approach currently uses a variant of the Adenosine Deaminase Acting on RNA (ADAR), naturally expressed enzymes in human cells that undertake physiological RNA editing functions. These deaminases convert adenosine bases to inosine in RNA, which is read as a guanosine in cellular processes such as translation and splicing [63]. This effectively creates an A > G edit in RNA and can be harnessed for the correction of G > A mutations. ADAR variants have also been engineered to create C > U edits: together, they can theoretically address up to 10% of known CHM mutations [64,65]. Harnessed for site-directed RNA editing, ADAR can be recruited to editing sites of interest by systems that link ADAR to an effector molecule and direct the ADAR-effector system with a gRNA to the base to be edited [54]. Many effectors have been developed including those based on CRISPR-Cas13 [65,66] or Cas9 systems [67], bacteriophage-derived λN peptide [71] and BoxB system, aptamer-like systems such as the MS2 bacteriophage coat protein (MCP) or GluR2 system [69]. Additionally, systems that deliver only a gRNA and use only endogenously expressed ADAR have been developed [69–71], in contrast [68] to other systems that require ADAR overexpression.
RNA A-to-I editing, environmental exposure, and human diseases
Published in Critical Reviews in Toxicology, 2021
RNA editing is a unique type of RNA modification and occurs in the specific nucleic acids of RNAs after transcription. There are two common forms of RNA editing in mammals including Adenosine to Inosine (A-to-I) and Cytidine to Uridine (C-to-U) conversion. RNA editing was initially discovered in the embryos of African clawed frog, Xenopus laevis, more than 30 years ago (Bass BL and Weintraub 1987; Rebagliati and Melton 1987). The first finding in human tissues was reported in 1987, regarding C-to-U conversion in the human mRNA of apolipoprotein-B48 gene in the intestine which was suggested as a tissue-specific modification of a single mRNA nucleotide (Powell et al. 1987). After these preliminary findings, RNA editing has been documented over three decades, leaving some aspects unexplored. Today, like several RNA modifications, such as m6A, RNA editing is associated with various diseases with limited findings. Furthermore, a few studies indicated that environmental stress could affect the RNA edition (Dorn et al. 2019). Together, we review a general overview of RNA editing- environmental exposures associations and RNA editing-diseases associations (cancer). This work presents initial evidence and raises awareness, thereby providing a comprehensive approach to understand the association between RNA A-to-I editing and environmental exposures and between RNA A-to-I editing and diseases, mainly cancer. By using the publicly available data, it also aims to present the association between environmental exposures and expression RNA A-to-I editing genes, and to provide the association between RNA A-to-I editing genes and cancer.