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.
Highlights
Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity
A wide range of neurodevelopmental disorders manifesting in infancy and early childhood or young adulthood are associated with disrupted interhemispheric communication, which in some but not all of the affected cases is accompanied by structural alterations of the corpus callosum, the brain’s largest commissure[1,2,3]
This gene is located in the chr. 11p13-14 neurodevelopmental risk locus and deleted in some cases of WAGR syndrome (Online Mendelian Inheritance of Man (OMIM) #194072), a rare copy number variant disorder with its core features caused by haploinsufficiency for the Wilms tumor 1 (WT1) and Paired box 6 (PAX6) homoebox gene[14]
Summary
Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. 22q11.2 micro-deletion or -duplication[8] as one of the most frequently diagnosed CNV in neuropsychiatric disease cohorts are affected by callosal hypoand hyperplasia[8] and interhemispheric dysconnectivity phenotypes have been associated with a rapidly increasing list of specific point mutations in cell surface signaling genes encoding key regulators of neurite outgrowth and connectivity, such as the Roundabout guidance receptor 1 (ROBO1)[9] or the L1 cell adhesion molecule (L1CAM)[10]. We show that C11orf[46] is, as an RNA-guided Cas[9] fusion protein, suitable for targeted epigenomic promoter editing to drive the expression of specific regulators of axonal development in immature transcallosal projection neurons, thereby offering a molecular tool to affect interhemispheric communication
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