Loss of Sfpq Causes Long-Gene Transcriptopathy in the Brain

Publication date: 1 May 2018
Source:Cell Reports, Volume 23, Issue 5
Author(s): Akihide Takeuchi, Kei Iida, Toshiaki Tsubota, Motoyasu Hosokawa, Masatsugu Denawa, J.B. Brown, Kensuke Ninomiya, Mikako Ito, Hiroshi Kimura, Takaya Abe, Hiroshi Kiyonari, Kinji Ohno, Masatoshi Hagiwara
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.

Graphical abstract

Teaser

It has been a long-standing question how mammalian neuronal cells achieve full gene length transcription of extra-long genes. Takeuchi et al. show that RNA-binding protein Sfpq sustains long-gene transcription through Pol II-CTD activation. Loss of Sfpq caused long-gene transcriptopathy, which could be the cause of neurodegenerative and psychiatric disorders.


https://ift.tt/2KPW3ur