Activation of endogenous retroviruses during brain development causes an inflammatory response, 2021, Jönsson et al

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Activation of endogenous retroviruses during brain development causes an inflammatory response

Marie E Jönsson, Raquel Garza, Yogita Sharma, Rebecca Petri, Erik Södersten, Jenny G Johansson, Pia A Johansson, Diahann AM Atacho, Karolina Pircs, Sofia Madsen, David Yudovich, Ramprasad Ramakrishnan, Johan Holmberg, Jonas Larsson, Patric Jern, Johan Jakobsson.

Abstract
Endogenous retroviruses (ERVs) make up a large fraction of mammalian genomes and are thought to contribute to human disease, including brain disorders. In the brain, aberrant activation of ERVs is a potential trigger for an inflammatory response, but mechanistic insight into this phenomenon remains lacking.

Using CRISPR/Cas9‐based gene disruption of the epigenetic co‐repressor protein Trim28, we found a dynamic H3K9me3‐dependent regulation of ERVs in proliferating neural progenitor cells (NPCs), but not in adult neurons.

In vivo deletion of Trim28 in cortical NPCs during mouse brain development resulted in viable offspring expressing high levels of ERVs in excitatory neurons in the adult brain.

Neuronal ERV expression was linked to activated microglia and the presence of ERV‐derived proteins in aggregate‐like structures.

This study demonstrates that brain development is a critical period for the silencing of ERVs and provides causal in vivo evidence demonstrating that transcriptional activation of ERV in neurons results in an inflammatory response.

https://www.embopress.org/doi/full/10.15252/embj.2020106423

 

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News article by Lund's Univeristy:

Activation of ancient viruses during brain development causes inflammation

https://www.multipark.lu.se/article...-during-brain-development-causes-inflammation

Researchers from Lund Stem Cell Center highlight the importance of controlling viral elements that reside in the genome and how their activation during development may contribute to brain disorders later in life. [...]

In a recent study, the Molecular Neurogenetics group - led by Prof. Johan Jakobsson - show dysregulation of ERVs during development can lead to both inflammations in the brain and gene expression patterns associated with various neurological disorders later in life.

“By using CRISPR-Cas9 gene editing technology we could generate several mouse models in which the silencing of specific ERVs is inactivated, either in the developing or in the adult brain,” explains Marie Jönsson, senior scientist and first author of the study recently published in the EMBO journal. [...]

“We observed that the active epigenetic silencing of ERVs is crucial during brain development, as these ancient viral elements were switched on and maintained their expression in the adult brain,” explains Marie.

Strikingly, the effects of ERV activation were not limited to neurons in which the epigenetic silencing was lost, but were also seen in adjacent cell types in which the epigenetic silencing was unaffected.

“When activated, ERVs produced not only genetic material but also proteins which agitated adjacent cells such as microglia - immune cells acting as a first line of defense for the brain and involved in processes such as inflammation.” continues Marie.