Topoisomerases facilitate transcription of long genes linked to autism

Ian F. King, Chandri N. Yandava, Angela M. Mabb, Jack S. Hsiao, Hsien-Sung Huang, Brandon L. Pearson, J. Mauro Calabrese, Joshua Starmer, Joel S. Parker, Terry Magnuson, Stormy J. Chamberlain, Benjamin D. Philpot () and Mark J. Zylka ()
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Ian F. King: The University of North Carolina at Chapel Hill
Chandri N. Yandava: Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill
Angela M. Mabb: The University of North Carolina at Chapel Hill
Jack S. Hsiao: University of Connecticut Health Center
Hsien-Sung Huang: The University of North Carolina at Chapel Hill
Brandon L. Pearson: The University of North Carolina at Chapel Hill
J. Mauro Calabrese: The University of North Carolina at Chapel Hill
Joshua Starmer: The University of North Carolina at Chapel Hill
Joel S. Parker: The University of North Carolina at Chapel Hill
Terry Magnuson: The University of North Carolina at Chapel Hill
Stormy J. Chamberlain: University of Connecticut Health Center
Benjamin D. Philpot: The University of North Carolina at Chapel Hill
Mark J. Zylka: The University of North Carolina at Chapel Hill

Nature, 2013, vol. 501, issue 7465, 58-62

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature12504

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