Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions
Sandhya Chandrasekaran, Sergio Espeso‐Gil, Yong‐Hwee Eddie Loh, Behnam Javidfar, Bibi Kassim, Yueyan Zhu, Yuan Zhang, Yuhao Dong, Lucy Bicks, Haixin Li, Prashanth Rajarajan, Cyril Peter, Daijing Sun, Esperanza Agulló-Pascual, Marina Iskhakova, Molly Estill, Bluma J. Lesch, Li Shen, Yan Jiang, Schahram Akbarian
Abstract
Abstract Regulatory mechanisms associated with repeat-rich sequences and chromosomal conformations in mature neurons remain unexplored. Here, we map cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B 2 NeuN+ megabase-scaling subcompartment. Single molecule long-read sequencing and comparative Hi-C chromosomal contact mapping in wild-derived SPRET/EiJ ( Mus spretus ) and laboratory inbred C57BL/6J ( Mus musculus ) reveal neuronal reconfigurations tracking recent ERV2 expansions in the murine germline, with significantly higher B 2 NeuN+ contact frequencies at sites with ongoing insertions in Mus musculus . Neuronal ablation of the retrotransposon silencer Kmt1e/Setdb1 triggers B 2 NeuN+ disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly with infiltration of dendrites . We conclude that neuronal megabase-scale chromosomal architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, results in transcriptional dysregulation and unleashes ERV2 proviruses with strong neuronal tropism.