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Topoisomerases facilitate transcription of long genes linked to autism.

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.

journal_name

Nature

journal_title

Nature

authors

King IF,Yandava CN,Mabb AM,Hsiao JS,Huang HS,Pearson BL,Calabrese JM,Starmer J,Parker JS,Magnuson T,Chamberlain SJ,Philpot BD,Zylka MJ

doi

10.1038/nature12504

subject

Has Abstract

pub_date

2013-09-05 00:00:00

pages

58-62

issue

7465

eissn

0028-0836

issn

1476-4687

pii

nature12504

journal_volume

501

pub_type

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