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The first conference on Transposable Elements in human brain evolution and diseases – December, 3rd 2021

Marie Jönnson, PhD
Disrupted ERV silencing during brain development results in an inflammatory response.
We used CRISPR/Cas9 to disrupt of the epigenetic co-repressor protein Trim28, both in the developing and the adult brain, and found a dynamic H3K9me3-dependent regulation of ERVs in proliferating neural progenitor cells (NPCs), but not in adult neurons. Transgenic in vivo deletion of Trim28 in cortical NPCs during mouse brain development resulted in high levels of ERVs in excitatory neurons in the adult brain. This neuronal ERV expression was linked to activated microglia and the presence of ERV-derived proteins in aggregate-like structures. Together, these results demonstrate that developmental silencing of ERVs is crucial for their maintained repression in the adult brain and provide causal in vivo evidence that transcriptional activation of ERVs in neurons results in both cell-intrinsic and cell-extrinsic effects as well as an inflammatory response.

Jose Luis Garcia-Perez, PhD
Retrotransposition in brain: does LINE activity in the central nervous system matter?
Transposable Elements (TEs) are stretches of DNA that can move within genomes. As pieces of mobile DNA, TE activity can change the genome of any species. Indeed, germline TE activity over evolution has significantly shaped the structure and function of the genome of all living organisms, including humans. Currently, active TEs in our germline genome (termed LINEs for Long Interspersed Elements) continue to generate genomic variability among humans. As a result, LINE activity continues to impact the functioning and regulation of our genome. As a type of selfish DNA, LINE activity is prominent in cellular niches that transmit genetic information to the next generation (i.e., germ cells and during early human embryogenesis). However, due to its mutagenic potential, the activity of LINE elements is tightly regulated, ensuring an equilibrium with the host. My laboratory aims to understand how active LINEs are regulated at the molecular level, and to infer the impact of their activity in relevant cellular models and model of disease. Surprisingly, it was recently demonstrated that active LINEs also move in neuronal cells of our brain (and of model organisms). These discoveries were unexpected, and suggest that the same mechanisms used to evolve germline genomes can act in our brain, but without leaving heritable traces. An emerging hypothesis suggests that TEs affect brain functionality, and my lab is using zebrafish to dissect how active TEs affect the vertebrate brain.

Fabio Macciardi, MD/PhD
Evolutionary lineage-specific regulatory functions of transposable elements (TEs) in the human brain.
Evidence is growing that regulation mediated by transposable elements (TEs) is a key process to control developmental gene-network not only in human embryonic stem cells, but also in the human brain. Previous studies revealed that TE-derived sequences, most notably from LTR7/HERV-H, LTR5-Hs, and L1HS, harbor many of the candidate human-specific regulatory loci with transcription factor binding sites (TFBS). We investigated TE-derived primate- and human-specific regulatory loci expression in the human neural tissue. We developed and validated a straightforward approach to identify unambiguous genome-wide expression profiles of discrete TEs in the human Dorsolateral Prefrontal Cortex (DLPFC) and in an in-vitro model of corticogenesis using de novo assembly. Then, we adopted a comparative genomics approach across humans, primates and rodents to identify conservation and lineage-specificity of transcriptionally-active TEs. We identified more than 650,000 transcripts expressed from more than 475,000 distinct TEs in the human DLPFC, and more than 400,000 TE transcripts in in-vitro neurons. We found that the vast majority of the expressed TEs (76.8% of all LINEs, 80.2% of all LTRs, 85.1% of all SINEs and 99.9% of all SVAs) are primate-specific. A relatively small number (n = 4,687) represent human-specific TEs, mostly L1HS, L1PA2, SVA and AluY, which together involve nearly half (48.7%) of all human-specific TE loci that are transcriptionally active in DLPFC. Our findings suggest that human brain structure and function evolved following distinctive trajectories and are congruent with the hypothesis that many incremental independent changes rather than one singular phenotype-defining event occurred in the human brains during the evolution of human lineage. A large set of DLPFC-expressed TE transcripts has been highly conserved for ~ 8 million years of primates’ evolution, likely conveying evolutionary-conserved primate-specific regulatory functions. A smaller set of human-specific TE transcripts became functional in more recent evolutionary times, suggesting that they could be relevant for human-specific behavioral or cognitive functions.

Cedric Feschotte, PhD
Transposons as a source of new genes and biological innovation in the vertebrate brain.
In this talk I will present data supporting the idea that transposon-derived sequences have been a continuous source of biological innovation during the evolution of the central nervous system of vertebrates, including humans. Notably I will highlight several protein-coding genes derived from transposable elements at different time points during chordate evolution that have been coopted specifically for brain function.  I will describe two ancient transposase-derived genes, PGBD5 and POGZ,  implicated in brain development and diseases including childhood tumors and autism respectively.  I will also discuss two genes, ARC and PNMA2, derived from retroviral-like Gag genes, that are expressed in neurons and capable of forming capsids that package their own RNA. It appears that ARC and PNMA2 are part of an elaborate system of trans-cellular RNA trafficking that is required for proper brain function, including memory formation.

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