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Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disease which is a highly heritable, but genetically heterogeneous. With increasing prevalence in last decade, it affects 1-2% population of the world, with the occurrence ratio of female to male being 1:4. Accumulating evidence suggests that ASD may be caused by synaptic dysfunction. At the same time, genes involved in synaptic function are often long genes (>100kb). Perturbation of long gene expression, and consequently synaptic homeostasis has been hypothesized to be involved in neurodevelopmental diseases. How the expression of long genes in the brain is regulated, and potentially altered in neurodevelopmental disorders remains unclear. Recent studies have shown that Topoisomerase 1 (TOP1), a ubiquitously expressed enzyme involved in DNA replication and repair, is required for the expression of long genes in neurons. However, whether this effect is cell-type specific in the brain has not been elucidated. Furthermore, genetic variants in topoisomerase genes have been identified in ASD individuals, raising a potential link between the dysregulation of long genes and TOP1 in ASD. The current study was carried out to (a) assess the cell-type specificity of TOP1’s effect on long gene transcription in the brain and (b) investigate the expression of TOP1 and TOP1-dependent genes in brain tissue from ASD and control individuals. By assessing the effect of TOP1 inhibition on long gene expression in glial cells (i.e. normal human astrocytes), the current study extended the role of TOP1 in regulating long gene expression to all major brain cell types and determined that the expression of long genes was inversely proportional to their length. We also demonstrate for the first time that TOP1 expression is enriched in the cerebellum compared to human cerebral cortex and that it is overexpressed in ASD brain samples. Furthermore, some of the TOP1-dependent genes also show increases in gene expression in ASD brain.