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      Retrotransposons in embryogenesis and neurodevelopment

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          Abstract

          Retrotransposable elements (RTEs) are genetic elements that can replicate and insert new copies into different genomic locations. RTEs have long been identified as ‘parasitic genes', as their mobilization can cause mutations, DNA damage, and inflammation. Interestingly, high levels of retrotransposon activation are observed in early embryogenesis and neurodevelopment, suggesting that RTEs may possess functional roles during these stages of development. Recent studies demonstrate that RTEs can function as transcriptional regulatory elements through mechanisms such as chromatin organization and noncoding RNAs. It is clear, however, that RTE expression and activity must be restrained at some level during development, since overactivation of RTEs during neurodevelopment is associated with several developmental disorders. Further investigation is needed to understand the importance of RTE expression and activity during neurodevelopment and the balance between RTE-regulated development and RTE-mediated pathogenesis.

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          Most cited references137

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          Initial sequencing and analysis of the human genome.

          The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
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            LINE-1 derepression in senescent cells triggers interferon and inflammaging

            Retrotransposable elements (RTEs) are deleterious at multiple levels, and failure of host surveillance systems can thus have negative consequences. However, the contribution of RTE activity to aging and age-associated diseases is not known. Here we show that during cellular senescence LINE-1 elements (L1s) become transcriptionally derepressed and activate a type-I interferon (IFN-I) response. The IFN-I response is a novel phenotype of late senescence and contributes to the maintenance of the senescence associated secretory phenotype (SASP). The IFN-I response is triggered by cytoplasmic L1 cDNA, and is antagonized by nucleoside reverse transcriptase inhibitors (NRTIs) that inhibit the L1 reverse transcriptase (RT). Treatment of aged mice with the NRTI lamivudine downregulated IFN-I activation and age-associated inflammation in several tissues. We propose that RTE activation is an important component of sterile inflammation that is a hallmark of aging, and that L1 RT is a relevant target for the treatment of age-associated disorders.
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              Reversal of neurological defects in a mouse model of Rett syndrome.

              Rett syndrome is an autism spectrum disorder caused by mosaic expression of mutant copies of the X-linked MECP2 gene in neurons. However, neurons do not die, which suggests that this is not a neurodegenerative disorder. An important question for future therapeutic approaches to this and related disorders concerns phenotypic reversibility. Can viable but defective neurons be repaired, or is the damage done during development without normal MeCP2 irrevocable? Using a mouse model, we demonstrate robust phenotypic reversal, as activation of MeCP2 expression leads to striking loss of advanced neurological symptoms in both immature and mature adult animals.

                Author and article information

                Journal
                Biochem Soc Trans
                Biochem Soc Trans
                BST
                Biochemical Society Transactions
                Portland Press Ltd.
                0300-5127
                1470-8752
                26 June 2024
                8 May 2024
                : 52
                : 3
                : 1159-1171
                Affiliations
                [1 ]Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
                [2 ]Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44195, U.S.A.
                Author notes
                Correspondence: Michelle S. Longworth ( longwom@ 123456ccf.org )
                Author information
                http://orcid.org/0000-0002-1313-1777
                Article
                BST-52-1159
                10.1042/BST20230757
                11346457
                38716891
                ae522625-45df-4592-bbb6-cf7030b3505b
                © 2024 The Author(s)

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). Open access for this article was enabled by the participation of Cleveland Clinic in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with Individual.

                History
                : 7 February 2024
                : 22 April 2024
                : 24 April 2024
                Categories
                Developmental Biology
                DNA, Chromosomes & Chromosomal Structure
                Embryology
                Gene Expression & Regulation
                Neuroscience
                RNA
                Stem Cells
                Review Articles

                Biochemistry
                line-1,neurodevelopment,neurodevelopmental disorders,retrotransposon
                Biochemistry
                line-1, neurodevelopment, neurodevelopmental disorders, retrotransposon

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