Human-specific regulation of neural maturation identified by cross-primate transcriptomics

Linker, Sara B.; Narvaiza, Iñigo; Hsu, Jonathan Y.; Wang, Meiyan; Qiu, Fan; Mendes, Ana Cristina; Oefner, Ruth; Kottilil, Kalyani; Sharma, Amandeep; Randolph‐Moore, Lynne; Mejia, Eunice; Santos, Renata; Marchetto, Maria C.; Gage, Fred H.

doi:10.1016/j.cub.2022.09.028

Cited by 11 publications

(7 citation statements)

References 59 publications

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“…We were not able to detect L1-lncRNA expression in chimpanzee fbNPCs. We verified the human-specific expression of this L1-lncRNA in previously published human, chimpanzee, bonobo, gorilla and macaque RNA-seq data from NPCs and immature neurons 47 and snRNA-seq from human, chimpanzee and macaque cerebral organoids 48 (Figure 5D&E). The L1-lncRNA was consistently expressed in human NPCs, immature neurons and organoids but not in cultures obtained from other primates.…”

Section: L1-derived Transcripts Contribute To Transcriptome Complexit...supporting

confidence: 82%

L1 retrotransposons drive human neuronal transcriptome complexity and functional diversification

Garza

Atacho

Adami

et al. 2023

Preprint

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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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Section: L1-derived Transcripts Contribute To Transcriptome Complexit...supporting

confidence: 82%

L1 retrotransposons drive human neuronal transcriptome complexity and functional diversification

Garza

Atacho

Adami

et al. 2023

Preprint

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show abstract

“…( D ) LINC01876 (L1-lncRNA) expression [transcripts per million (TPM)] from bulk RNA-seq of human, chimpanzee, bonobo, gorilla, and macaque rhesus NPCs from Linker et al. ( 47 ). ( E ) Percentage of cells expressing LINC01876 (L1-lncRNA) in human, chimpanzee, and macaque rhesus cerebral organoids from Kanton et al.…”

Section: Resultsmentioning

confidence: 99%

LINE-1 retrotransposons drive human neuronal transcriptome complexity and functional diversification

Garza,

Atacho,

Adami

et al. 2023

Sci. Adv.

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The genetic mechanisms underlying the expansion in size and complexity of the human brain remain poorly understood. Long interspersed nuclear element–1 (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 are largely unknown. Using multiomics profiling, we here demonstrate that L1 promoters are dynamically active in the developing and the adult human brain. L1s generate hundreds of developmentally regulated and cell type–specific transcripts, many that are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived long noncoding RNA, LINC01876 , is a human-specific transcript expressed exclusively during brain development. CRISPR interference 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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“…At the level of the LV transplants, the human-transplanted NPCs have migrated and adopted some specific trajectories toward the cortical zone before reaching a cortical destination. For the PFC-transplanted NPCs, the local and extrinsic factors were expected to increase the neuronal maturation while keeping the neotenic human phenotypes, which signifies that the xenografted cortical neurons are expected to retain some juvenile traits in adult mice [ 5 , 56 ].…”

Section: Resultsmentioning

confidence: 99%

Developmental Changes of Human Neural Progenitor Cells Grafted into the Ventricular System and Prefrontal Cortex of Mouse Brain in Utero

Pou

Thiberge

Zwan

et al. 2023

Cells

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The transplantation of neural progenitors into a host brain represents a useful tool to evaluate the involvement of cell-autonomous processes and host local cues in the regulation of neuronal differentiation during the development of the mammalian brain. Human brain development starts at the embryonic stages, in utero, with unique properties at its neotenic stages. We analyzed the engraftment and differentiation of human neuronal progenitor cells (hNPCs) transplanted in utero into the mouse brain. The influence of the environment was studied by transplanting human NPCs within the lateral ventricles (LV), compared with the prefrontal cortex (PFC) of immunocompetent mice. We developed a semi-automated method to accurately quantify the number of cell bodies and the distribution of neuronal projections among the different mouse brain structures, at 1 and 3 months post-transplantation (MPT). Our data show that human NPCs can differentiate between immature “juvenile” neurons and more mature pyramidal cells in a reproducible manner. Depending on the injection site, LV vs. PFC, specific fetal local environments could modify the synaptogenesis processes while maintaining human neoteny. The use of immunocompetent mice as host species allows us to investigate further neuropathological conditions making use of all of the engineered mouse models already available.

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Human-specific regulation of neural maturation identified by cross-primate transcriptomics

Cited by 11 publications

References 59 publications

L1 retrotransposons drive human neuronal transcriptome complexity and functional diversification

L1 retrotransposons drive human neuronal transcriptome complexity and functional diversification

LINE-1 retrotransposons drive human neuronal transcriptome complexity and functional diversification

Developmental Changes of Human Neural Progenitor Cells Grafted into the Ventricular System and Prefrontal Cortex of Mouse Brain in Utero

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