Evidence of shared transcriptomic dysregulation of HNRNPU-related disorder between human organoids and embryonic mice

Generating effective therapies for neurodevelopmental disorders has remained elusive. An emerging drug discovery approach for neurodevelopmental disorders is to characterize transcriptome-wide dysregulation in an appropriate model system and screen therapeutics based on their capacity to restore fun...

Full description

Saved in:
Bibliographic Details
Published in:iScience 2023-01, Vol.26 (1), p.105797, Article 105797
Main Authors: Ressler, Andrew K., Sampaio, Gabriela L.A., Dugger, Sarah A., Sapir, Tamar, Krizay, Daniel, Boland, Michael J., Reiner, Orly, Goldstein, David B.
Format: Article
Language:English
Subjects:
Biological sciences
Developmental biology
Embryology
Omics
Psychiatry
Transcriptomics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Generating effective therapies for neurodevelopmental disorders has remained elusive. An emerging drug discovery approach for neurodevelopmental disorders is to characterize transcriptome-wide dysregulation in an appropriate model system and screen therapeutics based on their capacity to restore functionally relevant expression patterns. We characterized transcriptomic dysregulation in a human model of HNRNPU-related disorder to explore the potential of such a paradigm. We identified widespread dysregulation in functionally relevant pathways and then compared dysregulation in a human model to transcriptomic differences in embryonic and perinatal mice to determine whether dysregulation in an in vitro human model is partially replicated in an in vivo model of HNRNPU-related disorder. Strikingly, we find enrichment of co-dysregulation between 45-day-old human organoids and embryonic, but not perinatal, mice from distinct models of HNRNPU-related disorder. Thus, hnRNPU deficient human organoids may only be suitable to model transcriptional dysregulation in certain cell types within a specific developmental time window. [Display omitted] •HNRNPU+/− hCOs are significantly smaller than wild-type organoids•HNRNPU+/− hCOs show increased number of dysregulated genes in precursor populations•Transcriptomic dysregulation in HNRNPU+/− hCOs concordant with embryonic mice•Embryonic and perinatal Hnrnpu mutant cortices do not show consistent dysregulation Psychiatry; Biological sciences; Developmental biology; Embryology; Omics; Transcriptomics
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2022.105797