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Cell Rep. 2018 May 1;23(5):1326-1341. doi: 10.1016/j.celrep.2018.03.141.

Loss of Sfpq Causes Long-Gene Transcriptopathy in the Brain.

Author information

1
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: takeuchi.akihide.8r@kyoto-u.ac.jp.
2
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.
3
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
4
Medical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
5
Laboratory for Molecular Biosciences, Life Science Informatics Research Unit, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
6
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
7
Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
8
Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan.
9
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.
10
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hagiwara.masatoshi.8c@kyoto-u.ac.jp.

Abstract

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.

KEYWORDS:

RBP/transcript-dependent elongation; RNA polymerase II; RNA-binding protein; cyclin-dependent kinase 9; long genopathies; long-gene diseases; long-gene transcriptotherapy; neurological and psychiatric diseases; neuronal development; transcriptional regulation

PMID:
29719248
DOI:
10.1016/j.celrep.2018.03.141
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