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In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene

Author

Listed:
  • Cyril J. Peter

    (Icahn School of Medicine at Mount Sinai)

  • Atsushi Saito

    (Johns Hopkins University School of Medicine)

  • Yuto Hasegawa

    (Johns Hopkins University School of Medicine)

  • Yuya Tanaka

    (Johns Hopkins University School of Medicine)

  • Mohika Nagpal

    (Johns Hopkins University School of Medicine)

  • Gabriel Perez

    (Johns Hopkins University School of Medicine)

  • Emily Alway

    (Johns Hopkins University School of Medicine)

  • Sergio Espeso-Gil

    (Icahn School of Medicine at Mount Sinai)

  • Tariq Fayyad

    (Icahn School of Medicine at Mount Sinai)

  • Chana Ratner

    (Icahn School of Medicine at Mount Sinai)

  • Aslihan Dincer

    (Icahn School of Medicine at Mount Sinai)

  • Achla Gupta

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

  • Lakshmi Devi

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

  • John G. Pappas

    (New York University School of Medicine)

  • François M. Lalonde

    (National Institute of Mental Health)

  • John A. Butman

    (The Clinical Center of the National Institutes of Health)

  • Joan C. Han

    (National Institute of Health
    University of Tennessee Health Science Center, and Children’s Foundation Research Institute, Le Bonheur Children’s Hospital)

  • Schahram Akbarian

    (Icahn School of Medicine at Mount Sinai)

  • Atsushi Kamiya

    (Johns Hopkins University School of Medicine)

Abstract

Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus. C11orf46 haploinsufficiency was associated with hypoplasia of the corpus callosum. C11orf46 knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, including Sema6a, were hyperexpressed in C11orf46-knockdown neurons. RNA-guided epigenetic editing of Sema6a gene promoters via a dCas9-SunTag system with C11orf46 binding normalized SEMA6A expression and rescued transcallosal dysconnectivity via repressive chromatin remodeling by the SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain’s connectome via gene-targeted designer activators and repressor proteins.

Suggested Citation

  • Cyril J. Peter & Atsushi Saito & Yuto Hasegawa & Yuya Tanaka & Mohika Nagpal & Gabriel Perez & Emily Alway & Sergio Espeso-Gil & Tariq Fayyad & Chana Ratner & Aslihan Dincer & Achla Gupta & Lakshmi De, 2019. "In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12013-y
    DOI: 10.1038/s41467-019-12013-y
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    Cited by:

    1. Yuto Hasegawa & Juhyun Kim & Gianluca Ursini & Yan Jouroukhin & Xiaolei Zhu & Yu Miyahara & Feiyi Xiong & Samskruthi Madireddy & Mizuho Obayashi & Beat Lutz & Akira Sawa & Solange P. Brown & Mikhail V, 2023. "Microglial cannabinoid receptor type 1 mediates social memory deficits in mice produced by adolescent THC exposure and 16p11.2 duplication," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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