L1 retrotransposons drive human neuronal transcriptome complexity and functional diversification

Garza, R.; Atacho, D.; Adami, A.; Gerdes, P.; Vinod, M.; Hsieh, P.; Karlsson, O.; Horvath, V.; Johansson, P. A.; Pandiloski, N.; Matas, J.; Quaegebeur, A.; Kouli, A.; Sharma, Y.; Jonsson, M. E.; Monni, E.; Englund, E.; Eichler, E. E.; Gale Hammell, M.; Barker, R. A.; Kokaia, Z.; Douse, C. H.; Jakobsson, J.

doi:10.1101/2023.03.04.531072

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bioRxiv · 10.1101/2023.03.04.531072

L1 retrotransposons drive human neuronal transcriptome complexity and functional diversification

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Abstract

The genetic mechanisms underlying the expansion in size and complexity of the human brain remains poorly understood. L1 retrotransposons are a source of divergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution is largely unknown. Using multi-omic profiling we here demonstrate that L1-promoters are dynamically active in the developing and adult human brain. L1s generate hundreds of developmentally regulated and cell-type specific transcripts, many which are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived lncRNA, LINC01876, is a human-specific transcript expressed exclusively during brain development. CRISPRi-silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human brain.

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Garza, R., Atacho, D., Adami, A., Gerdes, P., Vinod, M., Hsieh, P., Karlsson, O., Horvath, V., Johansson, P. A., Pandiloski, N., Matas, J., Quaegebeur, A., Kouli, A., Sharma, Y., Jonsson, M. E., Monni, E., Englund, E., Eichler, E. E., Gale Hammell, M., Barker, R. A., Kokaia, Z., Douse, C. H., Jakobsson, J.. 2023-03-06. L1 retrotransposons drive human neuronal transcriptome complexity and functional diversification. https://doi.org/10.1101/2023.03.04.531072

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