title: Topoisomerases facilitate transcription of long genes linked to autism.
abstract: Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically connected to ASD is unknown. Here we find that topotecan, a topoisomerase 1 (TOP1) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kilobases. Expression of long genes is also reduced after knockdown of Top1 or Top2b in neurons, highlighting that both enzymes are required for full expression of long genes. By mapping RNA polymerase II density genome-wide in neurons, we found that this length-dependent effect on gene expression was due to impaired transcription elongation. Interestingly, many high-confidence ASD candidate genes are exceptionally long and were reduced in expression after TOP1 inhibition. Our findings suggest that chemicals and genetic mutations that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders.
authors.affiliation: Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Ian F
authors.initials: IF
authors.lastname: King
authors.forename: Chandri N
authors.initials: CN
authors.lastname: Yandava
authors.forename: Angela M
authors.initials: AM
authors.lastname: Mabb
authors.forename: Jack S
authors.initials: JS
authors.lastname: Hsiao
authors.forename: Hsien-Sung
authors.initials: HS
authors.lastname: Huang
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Pearson
authors.forename: J Mauro
authors.initials: JM
authors.lastname: Calabrese
authors.forename: Joshua
authors.initials: J
authors.lastname: Starmer
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Terry
authors.initials: T
authors.lastname: Magnuson
authors.forename: Stormy J
authors.initials: SJ
authors.lastname: Chamberlain
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Philpot
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Zylka
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D004264:DNA Topoisomerases, Type I / Q000172:deficiency / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000172:deficiency / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D055785:Gene Knockdown Techniques; D018392:Genomic Imprinting / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D012319:RNA Polymerase II / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D059003:Topoisomerase Inhibitors / Q000494:pharmacology; D019772:Topotecan / Q000494:pharmacology; D061805:Transcription Elongation, Genetic / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D059003:Topoisomerase Inhibitors; D019772:Topotecan; D012319:RNA Polymerase II; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C000618814:TOP2B protein, human; C000618815:Top2b protein, mouse