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 () and Atsushi Kamiya ()
Additional contact information
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
Lakshmi Devi: 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
Schahram Akbarian: Icahn School of Medicine at Mount Sinai
Atsushi Kamiya: Johns Hopkins University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-019-12013-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12013-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-12013-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().