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Nat Commun. 2019 Sep 11;10(1):4112. doi: 10.1038/s41467-019-12013-y.

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

Author information

1
Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
2
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
3
Department of Pharmacology and System Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
4
Department of Pediatrics, New York University School of Medicine, New York, NY, USA.
5
Human Genetics Branch, National Institute of Mental Health, Bethesda, MD, 20892, USA.
6
Diagnostic Radiology Department, The Clinical Center of the National Institutes of Health, Bethesda, MD, 20892, USA.
7
Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, 20892, USA.
8
Departments of Pediatrics and Physiology, University of Tennessee Health Science Center, and Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN, 38103, USA.
9
Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. schahram.akbarian@mssm.edu.
10
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. akamiya1@jhmi.edu.

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.

PMID:
31511512
PMCID:
PMC6739341
DOI:
10.1038/s41467-019-12013-y
[Indexed for MEDLINE]
Free PMC Article

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