Topoisomerases facilitate transcription of long genes linked to autism
| Autor: | Chandri N. Yandava, Terry Magnuson, Joel S. Parker, Stormy J. Chamberlain, Benjamin D. Philpot, Hsien-Sung Huang, J. Mauro Calabrese, Angela M. Mabb, Mark J. Zylka, Jack S. Hsiao, Brandon L. Pearson, Joshua Starmer, Ian F. G. King |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Genetics
0303 health sciences Candidate gene CNTNAP2 Gene knockdown Multidisciplinary biology medicine.drug_class RNA polymerase II Article 03 medical and health sciences 0302 clinical medicine Gene expression mental disorders biology.protein medicine Genomic imprinting Gene 030217 neurology & neurosurgery Topoisomerase inhibitor 030304 developmental biology |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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. Reducing topoisomerase activity in mouse and human neurons is found to reduce the expression of long genes by impairing transcription elongation: among genes affected are numerous high-confidence candidates for autism spectrum disorder. Topoisomerases, enzymes involved in DNA winding, are expressed throughout the brain, and mutations have been discovered in some individuals with autism spectrum disorders (ASD). Mark Zylka and colleagues show that reducing topoisomerase activity selectively reduces the expression of long genes in mouse and human neurons by impairing transcription elongation. The authors note that many ASD candidate genes, including Cntnap2, Nrxn1 and Cntn4, are exceptionally long and confirm that expression of several ASD candidate genes is reduced by topoisomerase inhibition. These findings suggest that chemicals and genetic mutations that impair topoisomerases — and possibly other components of the transcription machinery — could contribute to ASD and other neurodevelopmental disorders. |
| Databáze: | OpenAIRE |
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