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

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 Devi, John G. Pappas, François M. Lalonde, John A. Butman, Joan C. Han, Schahram Akbarian, Atsushi Kamiya

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Number of pages1
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Sep 11 2019

Fingerprint

editing
Epigenomics
genes
chromatin
Chromatin
Chromatin Assembly and Disassembly
Genes
Connectome
loci
Repressor Proteins
Haploinsufficiency
Neuronal Plasticity
Gene encoding
Corpus Callosum
Chromosomes
Nuclear Proteins
proteins
disabilities
Intellectual Disability
Neurons

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene. / Peter, Cyril J.; Saito, Atsushi; Hasegawa, Yuto; Tanaka, Yuya; Nagpal, Mohika; Perez, Gabriel; Alway, Emily; Espeso-Gil, Sergio; Fayyad, Tariq; Ratner, Chana; Dincer, Aslihan; Gupta, Achla; Devi, Lakshmi; Pappas, John G.; Lalonde, François M.; Butman, John A.; Han, Joan C.; Akbarian, Schahram; Kamiya, Atsushi.

In: Nature communications, Vol. 10, No. 1, 11.09.2019.

Research output: Contribution to journalArticle

Peter, CJ, Saito, A, Hasegawa, Y, Tanaka, Y, Nagpal, M, Perez, G, Alway, E, Espeso-Gil, S, Fayyad, T, Ratner, C, Dincer, A, Gupta, A, Devi, L, Pappas, JG, Lalonde, FM, Butman, JA, Han, JC, Akbarian, S & Kamiya, A 2019, 'In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene', Nature communications, vol. 10, no. 1. https://doi.org/10.1038/s41467-019-12013-y
Peter, Cyril J. ; Saito, Atsushi ; Hasegawa, Yuto ; Tanaka, Yuya ; Nagpal, Mohika ; Perez, Gabriel ; Alway, Emily ; Espeso-Gil, Sergio ; Fayyad, Tariq ; Ratner, Chana ; Dincer, Aslihan ; Gupta, Achla ; Devi, Lakshmi ; Pappas, John G. ; Lalonde, François M. ; Butman, John A. ; Han, Joan C. ; Akbarian, Schahram ; Kamiya, Atsushi. / In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene. In: Nature communications. 2019 ; Vol. 10, No. 1.
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