Loss of Sfpq Causes Long-Gene Transcriptopathy in the Brain.
Cell Rep, 2018/05/01;23(5):1326-1341.
Takeuchi A[1], Iida K[2], Tsubota T[3], Hosokawa M[3], Denawa M[4], Brown JB[5], Ninomiya K[3], Ito M[6], Kimura H[7], Abe T[8], Kiyonari H[9], Ohno K[6], Hagiwara M[10]
Affiliations
PMID: 29719248DOI: 10.1016/j.celrep.2018.03.141
Impact factor: 9.995
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
MeSH terms
Animals; Apoptosis; Brain; Cyclin-Dependent Kinase 9; Introns; Mental Disorders; Mice; Mice, Knockout; Neurodegenerative Diseases; Neurons; PTB-Associated Splicing Factor; RNA Polymerase II; Transcription Elongation, Genetic
More resources
EndNote: Download