부산대학교 도서관

Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated global developmental delay, impaired ultrasonic vocalizations, cognitive dysfunction and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory neurons of the subiculum—a region of the hippocampus implicated in temporal lobe epilepsy. Evaluation of transcriptomic signature reversal as a therapeutic strategy highlights the potential importance of generating cell-type-specific signatures. Overall, this work provides insight into HNRNPU-mediated disease mechanisms and provides a framework for using single-cell RNA-sequencing to study transcriptional regulators implicated in disease. Author summary: The brain relies on strict regulation of gene expression for proper functioning. Mutations in genes that influence the expression of other genes are linked to neurological conditions such as epilepsy, autism, intellectual disability, and neurodegenerative disorders. Identifying targeted therapies for these genetic causes of disease are increasingly difficult since they often lead to a wide array of molecular and cellular effects from the widespread disturbance in gene expression. One potential approach is to identify therapies that shift the abnormal gene expression signature to a more normal state. To explore this 'transcriptome-guided' approach, we characterized the consequences of the loss of one copy of the gene expression regulator, HNRNPU, from the molecular to the whole organism level using a genetic mouse model. We generated disease-associated gene expression signatures and compared them to signatures obtained from cells treated with different drugs to pinpoint compounds with the potential to rescue abnormal gene expression. [ABSTRACT FROM AUTHOR]