The RNA-binding protein Sfpq regulates long neuronal genes in transcriptional elongation [RNA-seq]

Mammalian neurons express extra-long pre-mRNAs which are vulnerable to misregualtion of transcriptional elongation or processing but their regulation is still largely unknown. Here we found that RNA-binding protein PSF is specifically expressed in differentiated neuron of embryonic mouse brain and is essential for the expression of extra-long neuronal gene. HITS-CLIP indicated co-transcriptional binding of PSF to the nascent pre-mRNAs. When PSF was disrupted, pre-mRNA level of long genes was down-regulated in the middle of their transcripts toward their 3’ ends. In Pol II ChIP-Seq, decrease of the RNA polymerase II density was observed parallel to pre-mRNAs, indicating that transcriptional elongation was impaired. Loss of PSF caused massive apoptosis in embryonic mouse brains and heterozygous PSF mutant mice displayed schizophrenia-like abnormal behaviors. Gene Ontology analysis demonstrated that PSF-regulated genes have essential functions at the late developmental stage of brains. Our findings indicate that PSF is required for the neuronal development through facilitating the transcriptional elongation of extra-long neuronal genes and dysfunction of PSF could be a cause of neurodevelopmental and psychiatric disorders.