Journal Article Loss of Sfpq Causes Long-Gene Transcriptopathy in the Brain

Takeuchi, Akihide  ,  Iida, Kei  ,  Tsubota, Toshiaki  ,  Hosokawa, Motoyasu  ,  Denawa, Masatsugu  ,  Brown, J.B.  ,  Ninomiya, Kensuke  ,  Ito, Mikako  ,  Kimura, Hiroshi  ,  Abe, Takaya  ,  Kiyonari, Hiroshi  ,  Ohno, Kinji  ,  Hagiwara, Masatoshi

23 ( 5 )  , pp.1326 - 1341 , 2018-05-01 , Elsevier BV
神経巨大遺伝子の発現制御メカニズムの発見 --神経難病および精神疾患の病因解明と治療法開発に期待--. 京都大学プレスリリース. 2018-05-02.
Genes specifically expressed in neurons contain members with extended long introns. Longer genes present a problem with respect to fulfilment of gene length transcription, and evidence suggests that dysregulation of long genes is a mechanism underlying neurodegenerative and psychiatric disorders. Here, we report the discovery that RNA-binding protein Sfpq is a critical factor for maintaining transcriptional elongation of long genes. We demonstrate that Sfpq co-transcriptionally binds to long introns and is required for sustaining long-gene transcription by RNA polymerase II through mediating the interaction of cyclin-dependent kinase 9 with the elongation complex. Phenotypically, Sfpq disruption caused neuronal apoptosis in developing mouse brains. Expression analysis of Sfpq-regulated genes revealed specific downregulation of developmentally essential neuronal genes longer than 100 kb in Sfpq-disrupted brains; those genes are enriched in associations with neurodegenerative and psychiatric diseases. The identified molecular machinery yields directions for targeted investigations of the association between long-gene transcriptopathy and neuronal diseases.

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