LINE-1 retrotransposon activation intrinsic to interneuron development

Bodea, G. O.; Ferreiro, M. E.; Sanchez-Luque, F. J.; Botto, J. M.; Rasmussen, J.; Rahman, M. A.; Fenlon, L. R.; Gubert, C.; Gerdes, P.; Bodea, L.-G.; Ajjikuttira, P.; Kozulin, P.; Billon, V.; Morell, S.; Kempen, M.-J. H.; Love, C. J.; Palmer, L. M.; Ewing, A. D.; Jhaveri, D. J.; Richardson, S. R.; Hannan, A. J.; Faulkner, G. J.

doi:10.1101/2022.03.20.485017

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bioRxiv · 10.1101/2022.03.20.485017

LINE-1 retrotransposon activation intrinsic to interneuron development

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Abstract

Retrotransposons are a reservoir of cis-regulatory innovation1-3. Developmental programs that activate these elements could, in principle, manifest in lineage-specific retrotransposition. Somatic LINE-1 (L1) retrotransposon insertions have been detected in human and non-human primate neurons4-7. It is however unknown whether L1 is mobile in only some neuronal lineages, or therein regulates neurodevelopmental genes. Here, we report programmed L1 activation by SOX6, a transcription factor critical for parvalbumin (PV) interneuron development8-10. PV+ neurons permit L1 mobilization in vitro and in vivo, harbor unmethylated L1 promoters, and express full-length L1 mRNAs and proteins. Via nanopore long-read sequencing, we identify unmethylated L1 promoters proximal to PV+ neuron genes. One such L1, which promotes transcription of a novel CAPS2 gene isoform, significantly enhances neuron morphological complexity when phenotyped in vitro. These data highlight the contribution made by L1 cis-regulatory elements to PV+ neuron development and transcriptome diversity, uncovered due to L1 mobility in this milieu.

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Bodea, G. O., Ferreiro, M. E., Sanchez-Luque, F. J., Botto, J. M., Rasmussen, J., Rahman, M. A., Fenlon, L. R., Gubert, C., Gerdes, P., Bodea, L.-G., Ajjikuttira, P., Kozulin, P., Billon, V., Morell, S., Kempen, M.-J. H., Love, C. J., Palmer, L. M., Ewing, A. D., Jhaveri, D. J., Richardson, S. R., Hannan, A. J., Faulkner, G. J.. 2022-03-20. LINE-1 retrotransposon activation intrinsic to interneuron development. https://doi.org/10.1101/2022.03.20.485017

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