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Overexpression of LINE-1 Retrotransposons in Autism Brain

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Abstract

Long interspersed nuclear elements-1 (LINE-1 or L1) are mobile DNA sequences that are capable of duplication and insertion (retrotransposition) within the genome. Recently, retrotransposition of L1 was shown to occur within human brain leading to somatic mosaicism in hippocampus and cerebellum. Because unregulated L1 activity can promote genomic instability and mutagenesis, multiple mechanisms including epigenetic chromatin condensation have evolved to effectively repress L1 expression. Nonetheless, L1 expression has been shown to be increased in patients with Rett syndrome and schizophrenia. Based on this evidence and our reports of oxidative stress and epigenetic dysregulation in autism cerebellum, we sought to determine whether L1 expression was increased in autism brain. The results indicated that L1 expression was significantly elevated in the autism cerebellum but not in BA9, BA22, or BA24. The binding of repressive MeCP2 and histone H3K9me3 to L1 sequences was significantly lower in autism cerebellum suggesting that relaxation of epigenetic repression may have contributed to increased expression. Further, the increase in L1 expression was inversely correlated with glutathione redox status consistent with reports indicating that L1 expression is increased under pro-oxidant conditions. Finally, the expression of transcription factor FOXO3, sensor of oxidative stress, was significantly increased and positively associated with L1 expression and negatively associated with glutathione redox status. While these novel results are an important first step, future understanding of the contribution of elevated L1 expression to neuronal CNVs and genomic instability in autism will depend on emerging cell-specific genomic technologies, a challenge that warrants future investigation.

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Acknowledgements

We would like to thank the families of individuals with autism for the thoughtful donation of postmortem tissues to the Autism Tissue Program at the Harvard Brain Tissue Resource Center, Belmont, MA, and the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. This work was supported, in part, by the National Institute of Child Health and Development (RO1 HD051873 to SJJ) and the Jane Botsford Johnson Foundation.

The views expressed in this manuscript do not necessarily represent those of the US Food and Drug Administration.

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Authors and Affiliations

  1. Department of Pediatrics, Arkansas Children’s Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA

    Svitlana Shpyleva, Stepan Melnyk, Oleksandra Pavliv & S. Jill James

  2. National Center for Toxicological Research, Division of Biochemical Toxicology, Jefferson, AR, 72079, USA

    Igor Pogribny

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  1. Svitlana Shpyleva
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  2. Stepan Melnyk
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  3. Oleksandra Pavliv
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Correspondence to S. Jill James.

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Grant Sponsors: National Institute of Child Health and Development; Grant number: 1RO1HD051873; Arkansas Biosciences Institute; Jane Botsford Johnson Foundation

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Shpyleva, S., Melnyk, S., Pavliv, O. et al. Overexpression of LINE-1 Retrotransposons in Autism Brain. Mol Neurobiol 55, 1740–1749 (2018). https://doi.org/10.1007/s12035-017-0421-x

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