Topoisomerases facilitate transcription of long genes linked to autism
Nature (2013) doi:10.1038/nature12504
Received 17 January 2013 Accepted 24 July 2013 Published online 28 August 2013
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 & Mark J. Zylka
1Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599 USA
2Carolina Institute for Developmental Disabilities
3Department of Genetics and Developmental Biology, University of Connecticut Health Center,
Farmington, Connecticut 06032 USA
4Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North
Carolina 27599 USA
5Lineberger Comprehensive Cancer Center
6UNC Neuroscience Center
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.
