Topoisomerase I inhibition leads to length-dependent gene expression changes in human primary astrocytes

Abstract

Topoisomerase I is required for the proper expression of long genes (> 100 kb) in mouse and human cortical neurons, including many candidate genes for autism spectrum disorder (ASD) [1]. Given the important role of astrocytes in brain development [2], we investigated whether long genes, including autism susceptibility genes, also require topoisomerase I expression in human primary astrocytes. We carried genome-wide expression profiling of cultured human primary astrocytes following treatment with the topoisomerase I inhibitor Topotecan, using Illumina microarrays. We identified several thousands of differentially expressed genes and confirmed that topoisomerase I inhibition affects gene expression in human primary astrocytes in a length-dependent manner. We also identified over 20 ASD-associated genes that show topoisomerase-dependent gene expression in human primary astrocytes but have not been previously reported as topoisomerase-I-dependent in neurons. The microarray data have been deposited in NCBI GEO (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE90052.

Fig. 1

Length-dependent gene expression changes upon topotecan treatment. a) Scatterplot of log₂ fold changes at 24 h versus gene length. Each circle represents one differentially expressed gene. Red dots represent ASD genes. Red vertical line marks 100 kb. b) Boxplot of log₂ fold changes for genes differentially expressed at 24 h, binned by gene length. Green: genes shorter than 100 kb; red: genes longer than 100 kb.