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Author (up) King, I.F.; Yandava, C.N.; Mabb, A.M.; Hsiao, J.S.; Huang, H.-S.; Pearson, B.L.; Calabrese, J.M.; Starmer, J.; Parker, J.S.; Magnuson, T.; Chamberlain, S.J.; Philpot, B.D.; Zylka, M.J. url  doi
  Title Topoisomerases facilitate transcription of long genes linked to autism Type Journal Article
  Year 2013 Publication Nature Abbreviated Journal Nature  
  Volume 501 Issue 7465 Pages 58-62  
  Keywords Animals; Autistic Disorder/*genetics; DNA Topoisomerases, Type I/deficiency/*metabolism; DNA Topoisomerases, Type II/deficiency/metabolism; DNA-Binding Proteins/antagonists & inhibitors/deficiency/metabolism; Gene Knockdown Techniques; Genomic Imprinting/genetics; Humans; Mice; Mutation/genetics; RNA Polymerase II/metabolism; Synapses/metabolism; Topoisomerase Inhibitors/pharmacology; Topotecan/pharmacology; *Transcription Elongation, Genetic/drug effects  
  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.  
  Address Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0028-0836 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:23995680; PMCID:PMC3767287 Approved no  
  Call Number refbase @ user @ Serial 16875  
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