Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis.
Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis.
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影响异质核核糖核蛋白U（HNRNPU）的遗传变异已在几种神经发育障碍（NDD）中被发现。HNRNPU在人脑中广泛表达，并且在小脑中显示出最高的出生后表达。最近的研究已经研究了HNRNPU在大脑皮层发育中的作用，但HNRNPU缺乏对小脑发育的影响仍然未知。在这里，我们描述了HNRNPU基因座缺陷的分子和细胞的结果在体外神经分化的患者来源的和同基因的神经上皮干细胞与后脑配置文件。我们证明，HNRNPU缺陷导致染色质重塑的A/B区室，和转录重新布线，部分影响外显子包含在mRNA加工过程中。受染色质重组和宿主基因外显子使用差异影响的基因组区域显示出与癫痫、智力残疾和自闭症有关的基因的强烈富集。最后，我们表明，在细胞水平HNRNPU下调导致神经祖细胞在成熟的神经元群体的分数增加。我们的结论是，HNRNPU基因座参与延迟承诺的神经祖细胞分化的细胞类型与后脑的配置文件。总结：本研究揭示了HNRNPU在延迟后脑轮廓神经细胞的神经祖细胞分化中的作用。HNRNPU的缺乏与神经发育障碍有关，影响了mRNA加工过程中的染色质结构、转录重连和外显子使用，特别是富集了与癫痫、智力残疾和自闭症相关的基因。
Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role of HNRNPU in cerebral cortical development, but the effects of HNRNPU deficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes of HNRNPU locus deficiency during in vitro neural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level HNRNPU downregulation leads to an increased fraction of neural progenitors in the maturing neuronal population. We conclude that the HNRNPU locus is involved in delayed commitment of neural progenitors to differentiate in cell types with hindbrain profile. Summary: This study reveals the role of HNRNPU in delaying neural progenitor differentiation in hindbrain-profile neural cells. The deficiency of HNRNPU, linked to neurodevelopmental disorders, impacted chromatin structure, transcriptional rewiring, and exon usage during mRNA processing, particularly enriching genes associated with epilepsy, intellectual disability, and autism.
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