Evidence of shared transcriptomic dysregulation of HNRNPU-related disorder between human organoids and embryonic mice
Andrew K. Ressler,
Gabriela L.A. Sampaio,
Sarah A. Dugger,
Tamar Sapir,
Daniel Krizay,
Michael J. Boland,
Orly Reiner,
David B. Goldstein
Affiliations
Andrew K. Ressler
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Corresponding author
Gabriela L.A. Sampaio
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
Sarah A. Dugger
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
Tamar Sapir
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
Daniel Krizay
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
Michael J. Boland
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA
Orly Reiner
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel; Incumbent of the Berstein-Mason Professorial Chair of Neurochemistry, Head of M. Judith Ruth Institute of Preclinical Brain Research, Weizmann Institute of Science, Rehovot, Israel
David B. Goldstein
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
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.
