Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis
Author:
Mastropasqua FrancescaORCID, Oksanen MarikaORCID, Soldini Cristina, Alatar Shemim, Arora AbishekORCID, Ballarino RobertoORCID, Molinari Maya, Agostini FedericoORCID, Poulet AxelORCID, Watts MichelleORCID, Rabkina IelyzavetaORCID, Becker MartinORCID, Li DanyangORCID, Anderlid Britt-MarieORCID, Isaksson JohanORCID, Remnelius Karl Lundin, Moslem Mohsen, Jacob YannickORCID, Falk AnnaORCID, Crosetto NicolaORCID, Bienko MagdaORCID, Santini EmanuelaORCID, Borgkvist AndersORCID, Bölte SvenORCID, Tammimies KristiinaORCID
Abstract
ABSTRACTGenetic variants affectingHeterogeneous 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 ofHNRNPUin cerebral cortical development, but the effects ofHNRNPUdeficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes ofHNRNPUlocus deficiency duringin vitroneural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate thatHNRNPUdeficiency 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.HNRNPUdownregulation leads to altered neurogenesis and an increased fraction of neural progenitors in the maturing neuronal population. We conclude that,HNRNPUlocus is involved in delayed commitment of neural progenitors to neuronal maturation in cell types with hindbrain profile.
Publisher
Cold Spring Harbor Laboratory
Reference82 articles.
1. Spatial and cell type transcriptional landscape of human cerebellar development;Nat Neurosci,2021 2. Detecting differential usage of exons from RNA-seq data 3. Balasubramanian, M. , 2022. HNRNPU-Related Neurodevelopmental Disorder, in: Adam, M.P. , Everman, D.B. , Mirzaa, G.M. , Pagon, R.A. , Wallace, S.E. , Bean, L.J. , Gripp, K.W. , Amemiya, A. (Eds.), GeneReviews®. University of Washington, Seattle, Seattle (WA). 4. A Single-Cell Transcriptomic Map of the Human and Mouse Pancreas Reveals Inter- and Intra-cell Population Structure;Cell Syst,2016 5. Presynaptic dysfunction in CASK -related neurodevelopmental disorders;Translational Psychiatry,2020
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