Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis.
HNRNPU
HiC-sequencing
Hindbrain
Neurodevelopmental disorders
Neurogenesis
RNA-sequencing
Journal
Biology open
ISSN: 2046-6390
Titre abrégé: Biol Open
Pays: England
ID NLM: 101578018
Informations de publication
Date de publication:
15 10 2023
15 10 2023
Historique:
received:
25
08
2023
accepted:
04
09
2023
medline:
11
10
2023
pubmed:
10
10
2023
entrez:
10
10
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37815090
pii: 330791
doi: 10.1242/bio.060113
pmc: PMC10581386
pii:
doi:
Substances chimiques
Chromatin
0
Heterogeneous-Nuclear Ribonucleoprotein U
0
HNRNPU protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM128661
Pays : United States
Organisme : NIH HHS
ID : R35GM128661
Pays : United States
Informations de copyright
© 2023. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests M.B. is a full-time employee of Bayer AG, Germany. S.B. declares no direct conflict of interest related to this article. He discloses that he has, in the last 3 years, acted as an author, consultant, or lecturer for Medice and Roche. He receives royalties for textbooks and diagnostic tools from Hogrefe, and Liber. S.B. is shareholder in SB Education/Psychological Consulting AB and NeuroSupportSolutions International AB. The other authors have no conflicts to declare.
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