Loss of Sfpq Causes Long-Gene Transcriptopathy in the Brain
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
Affiliations
Akihide Takeuchi
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Corresponding author
Kei Iida
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Medical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Toshiaki Tsubota
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Motoyasu Hosokawa
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Masatsugu Denawa
Medical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
J.B. Brown
Laboratory for Molecular Biosciences, Life Science Informatics Research Unit, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Kensuke Ninomiya
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Mikako Ito
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Hiroshi Kimura
Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan
Takaya Abe
Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan
Hiroshi Kiyonari
Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan; Animal Resource Development Unit, R IKEN Center for Life Science Technologies, Kobe 650-0047, Japan
Kinji Ohno
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Masatoshi Hagiwara
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Corresponding author
Summary: 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. : 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. Keywords: RNA-binding protein, transcriptional regulation, RNA polymerase II, cyclin-dependent kinase 9, RBP/transcript-dependent elongation, long-gene transcriptotherapy, neuronal development, neurological and psychiatric diseases, long-gene diseases, long genopathies