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该基因座中的新基因。

: Novel Genes in the locus.

作者信息

Bach Svitlana V, Punzi Giovanna, Smith Nuri E, Mukherjee Sreya, Shin Joo Heon, Chen Qiang, Pertea Geo, Collado-Torres Leonardo, Maynard Kristen R, Page Stephanie C, Kleinman Joel E, Hyde Thomas M, Weinberger Daniel R, Martinowich Keri, Ursini Gianluca

机构信息

Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore (MD), USA.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore (MD), USA.

出版信息

medRxiv. 2025 Jul 14:2025.07.10.25331311. doi: 10.1101/2025.07.10.25331311.

Abstract

Divergent transcription from bidirectional promoters is frequently observed in eukaryotic genomes, but the biological relevance of divergent RNA transcripts (DT) is unknown. We identified and characterized , a novel DT gene, and , a novel readthrough gene, in the locus containing , a gene with key roles in neuronal development, differentiation, and synaptic plasticity. is independent from the known antisense (), and its expression is developmentally regulated and positively correlated with in human postmortem dorsolateral prefrontal cortex (DLPFC). and expression increase after induced depolarization, but the temporal dynamics follow expression of suggesting a regulatory role. Moreover, CRISPR-mediated upregulation of in human neural progenitor cells drives expression. Finally, shows higher expression in DLPFC from patients diagnosed with schizophrenia compared to neurotypical controls, and genetically predicted lower expression of the readthrough transcript is associated with schizophrenia and with the schizophrenia-associated C allele of the rs6265 single-nucleotide polymorphism. These data suggest that and contribute to regulation and schizophrenia risk.

摘要

双向启动子的发散转录在真核生物基因组中经常被观察到,但发散RNA转录本(DT)的生物学相关性尚不清楚。我们在包含一个在神经元发育、分化和突触可塑性中起关键作用的基因的基因座中鉴定并表征了一个新的DT基因和一个新的通读基因。该DT基因独立于已知的反义基因,其表达受发育调控,并且在人类死后背外侧前额叶皮层(DLPFC)中与该基因呈正相关。诱导去极化后,该DT基因和通读基因的表达增加,但时间动态遵循该基因的表达,提示其具有调节作用。此外,CRISPR介导的人类神经祖细胞中该DT基因的上调驱动了该基因的表达。最后,与神经典型对照相比,被诊断为精神分裂症的患者的DLPFC中该DT基因表达更高,并且遗传预测的通读转录本的低表达与精神分裂症以及与rs6265单核苷酸多态性的精神分裂症相关C等位基因有关。这些数据表明该DT基因和通读基因有助于该基因的调节和精神分裂症风险。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cd/12338882/bd2668130dee/nihpp-2025.07.10.25331311v1-f0001.jpg

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