Activation of endogenous retroviruses during brain development causes neuroinflammation

ABSTRACT: Endogenous retroviruses (ERVs) make up a large fraction of mammalian genome and are thought to contribute to human disease, including brain disorders. Aberrant activation of ERVs constitute a potential trigger for neuroinflammation, but mechanistic insight into this phenomenon remains unclear. 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 disruption of Trim28 in cortical NPCs during brain development resulted in viable offspring expressing high levels of ERVs in excitatory neurons in the adult brain of mice. Neuronal ERV expression was linked to inflammation, including activated microglia, and aggregates of ERV-derived proteins. 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 neuroinflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE154196 | GEO | 2021/02/24

REPOSITORIES: GEO