Deficiency of Heterogeneous Nuclear Ribonucleoprotein U leads to delayed neurogenesis

Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs); however, the role of HNRNPU in human neural development and NDDs remains to be studied. Here, we describe the molecular and cellular outcomes of HNRNPU deficiency during in vitro neural differentiation of isogenic and patient-derived neuroepithelial stem cells. 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 the effects of the molecular reorganization at the cellular level, where HNRNPU downregulation leads to altered neurogenesis and an increased fraction of neural progenitors marked in the maturing neuronal population. We conclude that HNRNPU deficiency is responsible for the delayed commitment of neural progenitors to neuronal maturation, ultimately leading to altered neurogenesis.