Scientific Understanding of Consciousness
Autism and the Transcription of Long Genes
Nature 501, 58–62 (05 September 2013)
Topoisomerases facilitate transcription of long genes linked to autism
Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Ian F. King, Angela M. Mabb, Hsien-Sung Huang, Brandon L. Pearson, Benjamin D. Philpot & Mark J. Zylka
Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Chandri N. Yandava, Benjamin D. Philpot & Mark J. Zylka
Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06032, USA
Jack S. Hsiao & Stormy J. Chamberlain
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
J. Mauro Calabrese, Joshua Starmer, Joel S. Parker & Terry Magnuson
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Joel S. Parker & Terry Magnuson
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Benjamin D. Philpot & Mark J. Zylka
Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
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.
Autism is a neurodevelopmental disorder with symptoms that include repetitive behaviours and deficits in social interactions. Hundreds of genes are now associated with ASD, suggesting that there are diverse genetic risk factors for autism. Environmental factors, including chemicals that are ingested during critical periods of brain development, can also increase autism risk. Many ASD candidate genes regulate synapse function; however, whether there are additional mechanisms that unite ASD patients or expression of ASD genes is unclear.
Mutations in topoisomerases were recently identified in some individuals with ASD. Topoisomerases are integral to gene expression, as they resolve DNA supercoiling that is generated during transcription. Here we sought to determine whether topoisomerases preferentially regulate the expression of additional imprinted genes in neurons, or whether they have broader effects on gene expression. Using genome-wide approaches, we unexpectedly found that topoisomerases facilitate the expression of long genes, including numerous long genes associated with synaptic function and ASD. In addition, our study uncovers a transcriptional mechanism that is particularly important for maintaining the expression of numerous ASD genes at normal levels.
Numerous genes associated with transcription are mutated in autism patients, although how these diverse transcriptional regulators contribute to autism is unclear. Our study highlights a mechanistic link between a critical step in transcription elongation and expression of numerous long ASD candidate genes. Our data suggest that chemicals or genetic mutations that impair topoisomerases, and possibly other components of the transcription elongation machinery that interface with topoisomerases, have the potential to profoundly affect the expression of long ASD candidate genes. Length-dependent impairment of gene transcription, particularly in neurons and during critical periods of brain development, may thus represent a unifying cause of pathology in many individuals with ASD and other neurodevelopmental disorders.
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