Repeat-rich sequence blocks are considered major determinants for 3D folding and structural genome organization in the cell nucleus in all higher eukaryotes. Here, we discuss how megabase-scale chromatin domain and chromosomal compartment organization in adult mouse cerebral cortex is linked, in highly cell type-specific fashion, to multiple retrotransposon superfamilies which comprise the vast majority of mobile DNA elements in the murine genome. We show that neuronal megadomain architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, unleashes proviruses from the Long Terminal Repeat (LTR) Endogenous Retrovirus family that exhibit strong tropism in mature neurons. Furthermore, we mapped, in the human brain, cell type-specific genomic integration patterns of the human pathogen and exogenous retrovirus, HIV, together with changes in genome organization and function of the HIV infected brain. Our work highlights the critical importance of chromosomal conformations and the ‘spatial genome’ for neuron- and glia-specific regulatory mechanisms and defenses aimed at exogenous and endogenous retrotransposons in the brain

Transposable elements, known colloquially as ‘jumping genes’, constitute approximately 45% of the human genome. Cells utilize epigenetic defenses to limit transposable element jumping, including formation of silencing heterochromatin and generation of piwi-interacting RNAs (piRNAs), small RNAs that facilitate clearance of transposable element transcripts. We have utilized fruit flies, mice and postmortem human brain samples to identify transposable element dysregulation as a key mediator of neuronal death in tauopathies, a group of neurodegenerative disorders that are pathologically characterized by deposits of tau protein in the brain. Mechanistically, we find that heterochromatin decondensation and reduction of piwi and piRNAs drive transposable element dysregulation in tauopathy. We further report a significant increase in transcripts of the endogenous retrovirus class of transposable elements in human Alzheimer’s disease and progressive supranuclear palsy, suggesting that transposable element dysregulation is conserved in human tauopathy. Taken together, our data identify heterochromatin decondensation, piwi and piRNA depletion and consequent transposable element dysregulation as a pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy.