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 K. Bicks, Haixin Li, Prashanth Rajarajan, Cyril J. Peter, Daijing Sun, Esperanza Agullo-Pascual, Marina Iskhakova, Molly Estill, Bluma J. Lesch, Li Shen, Yan Jiang () and Schahram Akbarian ()
Additional contact information
Sandhya Chandrasekaran: Icahn School of Medicine at Mount Sinai
Sergio Espeso-Gil: Icahn School of Medicine at Mount Sinai
Yong-Hwee Eddie Loh: Icahn School of Medicine at Mount Sinai
Behnam Javidfar: Icahn School of Medicine at Mount Sinai
Bibi Kassim: Icahn School of Medicine at Mount Sinai
Yueyan Zhu: Fudan University
Yuan Zhang: Fudan University
Yuhao Dong: Fudan University
Lucy K. Bicks: Icahn School of Medicine at Mount Sinai
Haixin Li: Yale School of Medicine
Prashanth Rajarajan: Icahn School of Medicine at Mount Sinai
Cyril J. Peter: Icahn School of Medicine at Mount Sinai
Daijing Sun: Fudan University
Esperanza Agullo-Pascual: Icahn School of Medicine at Mount Sinai
Marina Iskhakova: Icahn School of Medicine at Mount Sinai
Molly Estill: Icahn School of Medicine at Mount Sinai
Bluma J. Lesch: Yale School of Medicine
Li Shen: Icahn School of Medicine at Mount Sinai
Yan Jiang: Fudan University
Schahram Akbarian: Icahn School of Medicine at Mount Sinai

Nature Communications, 2021, vol. 12, issue 1, 1-16

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 B2NeuN+ 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 B2NeuN+ contact frequencies at sites with ongoing insertions in Mus musculus. Neuronal ablation of the retrotransposon silencer Kmt1e/Setdb1 triggers B2NeuN+ 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.

Date: 2021
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DOI: 10.1038/s41467-021-26862-z

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