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Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions

Author

Listed:
  • Sandhya Chandrasekaran

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Sergio Espeso-Gil

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Yong-Hwee Eddie Loh

    (Icahn School of Medicine at Mount Sinai
    University of Southern California)

  • Behnam Javidfar

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Bibi Kassim

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Yueyan Zhu

    (Fudan University)

  • Yuan Zhang

    (Fudan University
    Fudan University Pudong Medical Center)

  • Yuhao Dong

    (Fudan University)

  • Lucy K. Bicks

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Haixin Li

    (Yale School of Medicine
    Tongji University School of Medicine)

  • Prashanth Rajarajan

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Cyril J. Peter

    (Icahn School of Medicine at Mount Sinai
    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
    Icahn School of Medicine at Mount Sinai)

  • Molly Estill

    (Icahn School of Medicine at Mount Sinai)

  • Bluma J. Lesch

    (Yale School of Medicine
    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
    Icahn School of Medicine at Mount Sinai)

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.

Suggested Citation

  • 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. Pet, 2021. "Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26862-z
    DOI: 10.1038/s41467-021-26862-z
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    2. Beatriz del Blanco & Sergio Niñerola & Ana M. Martín-González & Juan Paraíso-Luna & Minji Kim & Rafael Muñoz-Viana & Carina Racovac & Jose V. Sanchez-Mut & Yijun Ruan & Ángel Barco, 2024. "Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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