Editors' ChoiceAutism

Length Matters

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Science Translational Medicine  02 Oct 2013:
Vol. 5, Issue 205, pp. 205ec163
DOI: 10.1126/scitranslmed.3007665

Autism spectrum disorders (ASDs) are neurodevelopmental disorders that are characterized by impaired social interactions and communication and the presence of stereotypical behaviors. Although hundreds of candidate genes as well as environmental factors have been implicated in ASDs, a new study by King et al. points to a linear explanation of a potential cause. Transcribed genes differ greatly in length, and hence, “pulling” the RNA polymerase II (Pol II) along the “long” genes may require additional factors compared with transcription of “short” genes. Topoisomerases are expressed throughout the developing brain and catalyze the unwinding of supercoiled DNA sequences during transcription. Recent sequencing efforts and the new study by King et al. now reveal an association between mutations in the genes encoding topoisomerase enzymes and ASDs.

The King et al. study suggests that topoisomerase-mediated DNA unwinding is important for the expression of extremely long genes in mouse and human neurons. The authors found that both inhibition or loss of topoisomerases resulted in widespread suppression of the transcriptional elongation of genes >67 kb in length. The level of suppression appeared to correlate with gene length. Importantly, ~30% of the topoisomerase-dependent long genes are associated as candidate genes with ASDs. Although the exact mechanism by which topoisomerases contribute to transcription remains elusive, genome-wide mapping of Pol II (an enzyme associated with topoisomerase and required for transcriptional elongation) reveals specific loss of Pol II from long genes upon inhibition of topoisomerases. These results suggest that topoisomerases are required for efficient Pol II–dependent elongation of long genes. The most straightforward model could involve the cotranscriptional unwinding of supercoiled DNA.

King et al. describe a fundamentally new role for topoisomerases in mammalian gene regulation. Connecting the length-dependent efficiency of transcriptional elongation and development of ASDs may help to develop new therapeutic strategies that boost gene expression regulation during critical developmental periods. RNA elongation is controlled by many factors, including suppressors of elongation. Therefore, pharmacological inhibition of suppressors of RNA elongation could improve transcription of genes affected by mutations in positive regulators of elongation such as topoisomerases.

I. F. King et al., Topoisomerases facilitate transcription of long genes linked to autism. Nature 501, 58–62 (2013). [Abstract]

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