DOI: 10.1101/491779Dec 10, 2018Paper

In vivo epigenetic editing of sema6a promoter reverses impaired transcallosal connectivity caused by C11orf46/ARL14EP neurodevelopmental risk gene

BioRxiv : the Preprint Server for Biology
Cyril J. PeterAtsushi Kamiya

Abstract

Many neuropsychiatric risk genes contribute to epigenetic regulation of gene expression but very little is known about specific chromatin-associated mechanisms governing the formation and maintenance of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46 (also known as ARL14EP ), a small nuclear protein encoded in the chromosome 11p13 Wilms Tumor, Aniridia, Genitourinary Abnormalities, intellectual disability (formerly referred to as Mental Retardation) (WAGR) risk locus. C11orf46 haploinsufficiency in WAGR microdeletion cases was associated with severe hypoplasia of the corpus callosum. In utero short hairpin RNA-mediated C11orf46 knockdown disrupted transcallosal projections of cortical pyramidal neurons, a phenotype that was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with autosomal recessive intellectual disability. Multiple genes encoding key regulators of axonal growth and differentiation, including Sema6A , were hyperexpressed in C11orf46-knockdown neurons. Importantly, RNA-guided epigenetic editing of neuronal Sema6a gene promoters via a dCas9 protein-conjugated SunTag scaffold with multimeric (10x) C11orf46 binding during early developmen...Continue Reading

Related Concepts

Brain
Cell Differentiation Process
Chromatin
Corpus Callosum
Experimental Design
Gene Expression
Genes
Mental Retardation
Nephroblastoma
Neurons

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