Loss of Sfpq Causes Long-Gene Transcriptopathy in the Brain

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Brain* / metabolism
  • Brain* / pathology
  • Cyclin-Dependent Kinase 9 / metabolism
  • Introns
  • Mental Disorders* / genetics
  • Mental Disorders* / metabolism
  • Mental Disorders* / pathology
  • Mice
  • Mice, Knockout
  • Neurodegenerative Diseases* / genetics
  • Neurodegenerative Diseases* / metabolism
  • Neurodegenerative Diseases* / pathology
  • Neurons / metabolism*
  • Neurons / pathology
  • PTB-Associated Splicing Factor / deficiency*
  • PTB-Associated Splicing Factor / metabolism
  • RNA Polymerase II / metabolism
  • Transcription Elongation, Genetic*


  • PTB-Associated Splicing Factor
  • Cdk9 protein, mouse
  • Cyclin-Dependent Kinase 9
  • RNA Polymerase II