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  • 1
    Publication Date: 2013-09-03
    Description: 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.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉King, Ian F -- Yandava, Chandri N -- Mabb, Angela M -- Hsiao, Jack S -- Huang, Hsien-Sung -- Pearson, Brandon L -- Calabrese, J Mauro -- Starmer, Joshua -- Parker, Joel S -- Magnuson, Terry -- Chamberlain, Stormy J -- Philpot, Benjamin D -- Zylka, Mark J -- P30 NS045892/NS/NINDS NIH HHS/ -- P30HD03110/HD/NICHD NIH HHS/ -- P30NS045892/NS/NINDS NIH HHS/ -- R01 GM101974/GM/NIGMS NIH HHS/ -- R01 HD068730/HD/NICHD NIH HHS/ -- R01 MH093372/MH/NIMH NIH HHS/ -- R01GM101974/GM/NIGMS NIH HHS/ -- R01HD068730/HD/NICHD NIH HHS/ -- R01MH093372/MH/NIMH NIH HHS/ -- T32 HD040127/HD/NICHD NIH HHS/ -- T32HD040127/HD/NICHD NIH HHS/ -- England -- Nature. 2013 Sep 5;501(7465):58-62. doi: 10.1038/nature12504. Epub 2013 Aug 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    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
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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