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Epigenetic Reprogramming in Early Embryo Development
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
In eukaryotes, two main types of TEs have been described, retrotransposons and DNA transposons. DNA transposons or class II TEs move by a simple “cut and paste” mechanism: A DNA transposon sequence is removed from one genomic location and inserted in a new genomic site, using a specialized protein termed transposase (67). Its proportion in the human and mouse genome is lower than 5%, and no active DNA-transposons are present in these genomes at present. On the other hand, retrotransposons, or class I TEs, move by a “copy and paste” mechanism of mobilization that requires reverse transcription of an intermediate TEs RNA. In the human and mouse, more than 95% of TEs belong to this class (66) and represent more than 35% of the genome (68).
Epigenetics, Nutrition, and Infant Health
Published in Crystal D. Karakochuk, Kyly C. Whitfield, Tim J. Green, Klaus Kraemer, The Biology of the First 1,000 Days, 2017
Philip T. James, Matt J. Silver, Andrew M. Prentice
There are some regions of the genome that demonstrate increased interindividual epigenetic variation, and may be particularly vulnerable to the impact of environmental influences [19]. These include imprinted genes, metastable epialleles, and transposable elements. Imprinted genes show monoallelic expression, whereby only the maternally or paternally inherited allele is expressed [20]. If a gene is “paternally expressed” it means the expressed allele comes from the father and the maternal allele is imprinted (silenced). In regard to growth, paternally expressed genes tend to promote in utero growth, whereas maternally expressed genes restrict growth, and this forms the basis of the “parental conflict theory” [21]. Metastable epialleles (MEs) are genomic loci whose methylation state varies between individuals, but where variation is correlated across tissues originating from all germ layers in a single individual [22]. This indicates that the marks have been laid down in the first few days after conception before cell types start to specialize. MEs therefore provide a useful device to study the influence of the periconceptional environment, including maternal nutrition, on the offspring epigenome [23,24]. Transposable elements (TEs) are small pieces of DNA (usually of viral origin earlier in human history) that are mobile and can insert into new chromosomal locations throughout the genome. They are thought to make up more than half of the human genome [25]. TEs arise either through the use of RNA as an intermediate for transposition (DNA is transcribed to RNA, reverse transcribed to DNA, and then inserted by reverse transcriptase to form a retrotransposon), or through the complete DNA sequence being cut and pasted directly (forming DNA transposons, which are less common in the human genome). TEs are potentially functionally disruptive, for example, if transposed into a functional gene or when increasing copy number, and this may be one reason why most are silenced epigenetically [26]. Some TEs are thought to be vulnerable to the influence of nutrition at key time points [27], and their variable methylation patterns have been shown to affect neighboring gene expression, most notably in the Agouti mouse experiments detailed later in this chapter.
Effects of the COVID-19 pandemic: new approaches for accelerated delivery of gene to first-in-human CMC data for recombinant proteins
Published in mAbs, 2023
Hervé Broly, Jonathan Souquet, Alain Beck
There is now accumulated evidence on the limited risk of genetic instability, non-reproducibility, and non-comparability between non-clonally derived preclinical and clonally derived Phase 1 materials if an appropriate cell line development strategy has been applied. Therefore, there are some precautions to take before implementing a non-clonal strategy for the production of preclinical material. One could consider cell engineering methods, such as transduction, DNA transposon integration or SSI, to deliver stable pools with high levels of cell homogeneity and a lower risk of significant genetic diversity and instability of expression. Alternatively, transfecting engineered parental cells with a GS double knockout allows higher stability of expression than wild-type parental cells. In addition, selecting the final manufacturing cell line by screening clones derived from the cell pool used for producing preclinical material may further minimize the risk of non-comparability between preclinical and Phase 1 materials.94
New frontiers in precision medicine for Sjogren’s syndrome
Published in Expert Review of Clinical Immunology, 2021
Loukas Chatzis, Panayiotis G Vlachoyiannopoulos, Athanasios G Tzioufas, Andreas V Goules
Lately, the contribution of innate immunity to the pathogenesis of Sjogren Syndrome has been studied extensively, focusing mainly on the role of interferons (IFNs) and plasmacytoid dendritic cells (pDCs) as the primary source of IFNα. Type I IFNs are known to modify the immune system and affect the function of many cell types. The presence of type I IFN-inducible genes was initially documented at the MSG level in SS patients, while type I IFN signature was also detected in PBMCs, B cells, and monocytes of peripheral blood along with elevated plasma levels of IFNα/β [62,63]. Interestingly, interferon type I and II induced protein activity was detected in ductal epithelial cells, while the inflammatory infiltrate surrounding the inflamed ducts produced type II only activity, supporting a dual role of the two types of interferons upon the diseased epithelium [64,65]. In accordance, pDCs have been identified in the MSG of SS patients and there is evidence that they can be activated through endogenous free DNA, transposons, or nucleic acid containing immune complexes. Recently, type III IFNs and especially interferon λ2 bearing similar immune modifying functions as type I IFNs were found to be upregulated within the inflammatory sites of MSG due to TLR3 ligation of the epithelial cells [66]. The pluripotent role of all types of INFs in SS, as well as the potential inhibition of several molecules in their complex pathways as a novel therapeutic approach, is nicely reviewed by Bodewes and Versnel [67,68].
Effects of ionizing radiation at Drosophila melanogaster with differently active hobo transposons
Published in International Journal of Radiation Biology, 2019
Transposable elements (TEs) are mobile DNA fragments of genome. The classification of TEs is based on differences in their structure and mechanisms of movement in the genome. Currently, there are three classes of TEs (Kim 2014). The first class includes retrotransposons — long terminal repeat (LTR)-retrotransposons (gypsy, copia et al.), non-LTR-retrotransposons and retroviruses (I, jockey, LINEs, SINEs et al.), and retroelements (PLEs). Mechanism (DNA-RNA-DNA displacement) of their movement is associated with the synthesis of DNA chain through the formation of RNA mediator with the participation of the enzyme reverse transcriptase (Finnegan 1989). The second class of TEs is represented by DNA transposons (P, hobo, mariner et al.) encoding a transposase. A transposase is able to recognize the ends of ‘its’ element, cut it out of the chromosome and/or embed it into the chromosome of the host genome (Bazin et al. 1999). Such a mechanism of transposition (DNA-DNA displacement) leads to DNA integrity disruption and the formation of double-stranded breaks (Kaufman and Rio 1992; Khromykh et al. 2004). The third class includes helitrons and polintons which move along the genome on the rolling circle replication (Jurka et al. 2007). In some papers, passive elements of the foldback (FB) type are considered as a separate class TEs. FBs found only in plants and in the genomes of the melanogaster subgroup flies (Macas et al. 2003; Badal et al. 2013). They are distinguished by the presence of large arrays of short terminally inverted repeat (TIRs), possibly representing nonhomologous recombination targets. Mechanism of their movement is still unknown. There is an opinion that when the FB moves, a so-called ‘complex with paired ends of the transposon’ is formed the transpososome (Kim 2014).