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

Abstract

AbstractMany 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 onC11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus.C11orf46haploinsufficiency was associated with hypoplasia of the corpus callosum.C11orf46knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46R236Hmutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, includingSema6a, were hyperexpressed inC11orf46-knockdown neurons. RNA-guided epigenetic editing ofSema6agene 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.