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Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis

Mastropasqua, Francesca ; Oksanen, Marika ; Soldini, Cristina ; Alatar, Shemim ; Arora, Abishek ; Ballarino, Roberto ; Molinari, Maya ; Agostini, Federico ; Poulet, Axel and Watts, Michelle , et al. (2023) In Biology Open 12(10).
Abstract

Genetic variants affectingHeterogeneousNuclear RibonucleoproteinU (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,... (More)

Genetic variants affectingHeterogeneousNuclear RibonucleoproteinU (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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
HiC-sequencing, Hindbrain, HNRNPU, Neurodevelopmental disorders, Neurogenesis, RNA-sequencing
in
Biology Open
volume
12
issue
10
article number
bio060113
publisher
The Company of Biologists Ltd
external identifiers
  • pmid:37815090
  • scopus:85187921546
ISSN
2046-6390
DOI
10.1242/bio.060113
language
English
LU publication?
yes
id
9b13b686-1554-4f1e-bbad-18e803ccbcbc
date added to LUP
2024-03-28 09:57:36
date last changed
2024-04-26 13:52:39
@article{9b13b686-1554-4f1e-bbad-18e803ccbcbc,
  abstract     = {{<p>Genetic variants affectingHeterogeneousNuclear RibonucleoproteinU (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.</p>}},
  author       = {{Mastropasqua, Francesca and Oksanen, Marika and Soldini, Cristina and Alatar, Shemim and Arora, Abishek and Ballarino, Roberto and Molinari, Maya and Agostini, Federico and Poulet, Axel and Watts, Michelle and Rabkina, Ielyzaveta and Becker, Martin and Li, Danyang and Anderlid, Britt Marie and Isaksson, Johan and Remnelius, Karl Lundin and Moslem, Mohsen and Jacob, Yannick and Falk, Anna and Crosetto, Nicola and Bienko, Magda and Santini, Emanuela and Borgkvist, Anders and Bölte, Sven and Tammimies, Kristiina}},
  issn         = {{2046-6390}},
  keywords     = {{HiC-sequencing; Hindbrain; HNRNPU; Neurodevelopmental disorders; Neurogenesis; RNA-sequencing}},
  language     = {{eng}},
  number       = {{10}},
  publisher    = {{The Company of Biologists Ltd}},
  series       = {{Biology Open}},
  title        = {{Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis}},
  url          = {{http://dx.doi.org/10.1242/bio.060113}},
  doi          = {{10.1242/bio.060113}},
  volume       = {{12}},
  year         = {{2023}},
}