HNRNPH2-R114W remodels RNA splicing and neurodevelopmental gene programs in isogenic cerebral organoids
5 affiliations
- 1Dell Pediatric Research Institute, University of Texas at Austin , , ,
- 2To Cure a Rose Foundation, Austin Community College , , ,
- 3Computational Systems Biology Laboratory, Universidade de São Paulo , ,
- 4Baylor College of Medicine, Center for Precision Environmental Health , , ,
- 5AlphaRose Therapeutics , , ,
Abstract
Autism spectrum disorder has been linked to disrupted RNA processing during corticogenesis, yet variant-specific mechanisms remain difficult to resolve. Isogenic cerebral organoids derived from a patient-derived induced pluripotent stem cell (iPSC) line carrying the HNRNPH2-R114W variant and its CRISPR-corrected counterpart serve as a human developmental model to investigate variant-associated RNA dysregulation. Imaging quantification and exploratory bulk RNA sequencing, performed at a single developmental time point on a pooled organoid RNA from each genotype, identify coordinated remodeling of neuronal and metabolic programs, along with junction-centered splicing dysregulation involving 6,310 differentially used junctions. Computational structural docking situates HNRNPH2 RNA recognition motifs (RRMs) 1–3 within a spliceosomal context and locates residue R114 near a predicted RNA-contact interface, indicating that the R114W substitution may alter RNA engagement. Integration of differential expression with event- and isoform-level analyses identifies regulatory hubs enriched for axon guidance and synaptic signaling pathways. Single-cell-reference-based deconvolution suggests modest compositional shifts that are unlikely to account for the extent of transcriptional and splicing alterations observed. Collectively, these findings imply HNRNPH2-R114W in widespread RNA rewiring and define candidate isoform-level endpoints for mechanistic and therapeutic investigation in human cortical organoids. These molecular signatures open new avenues to examine how HNRNPH2-associated RNA dysregulation evolves across developmental time and recurs across independent biological contexts, providing a foundation for further mechanistic studies of this rare neurodevelopmental disorder.
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BibTeX
@article{caiaffa2026hnrnph2r114w,
title = {{HNRNPH2-R114W remodels RNA splicing and neurodevelopmental gene programs in isogenic cerebral organoids}},
author = {Carlo Donato Caiaffa and Neda Ghousifam and Stephan Lloyd Watkins and Helder I. Nakaya and Rodney A. Bowling and Richard H. Finnell and Robert M. Cabrera},
journal = {Frontiers in bioengineering and biotechnology},
year = {2026},
month = oct,
doi = {10.3389/fbioe.2026.1922305},
url = {https://europepmc.org/article/PMC/PMC13719587},
note = {CC BY},
}
RIS
TY - JOUR
TI - HNRNPH2-R114W remodels RNA splicing and neurodevelopmental gene programs in isogenic cerebral organoids
AU - Carlo Donato Caiaffa
AU - Neda Ghousifam
AU - Stephan Lloyd Watkins
AU - Helder I. Nakaya
AU - Rodney A. Bowling
AU - Richard H. Finnell
AU - Robert M. Cabrera
PY - 2026
DA - 2026/10/16
JO - Frontiers in bioengineering and biotechnology
DO - 10.3389/fbioe.2026.1922305
UR - https://europepmc.org/article/PMC/PMC13719587
AB - Autism spectrum disorder has been linked to disrupted RNA processing during corticogenesis, yet variant-specific mechanisms remain difficult to resolve. Isogenic cerebral organoids derived from a patient-derived induced pluripotent stem cell (iPSC) line carrying the HNRNPH2-R114W variant and its CRISPR-corrected counterpart serve as a human developmental model to investigate variant-associated RNA dysregulation. Imaging quantification and exploratory bulk RNA sequencing, performed at a single developmental time point on a pooled organoid RNA from each genotype, identify coordinated remodeling of neuronal and metabolic programs, along with junction-centered splicing dysregulation involving 6,310 differentially used junctions. Computational structural docking situates HNRNPH2 RNA recognition motifs (RRMs) 1–3 within a spliceosomal context and locates residue R114 near a predicted RNA-contact interface, indicating that the R114W substitution may alter RNA engagement. Integration of differential expression with event- and isoform-level analyses identifies regulatory hubs enriched for axon guidance and synaptic signaling pathways. Single-cell-reference-based deconvolution suggests modest compositional shifts that are unlikely to account for the extent of transcriptional and splicing alterations observed. Collectively, these findings imply HNRNPH2-R114W in widespread RNA rewiring and define candidate isoform-level endpoints for mechanistic and therapeutic investigation in human cortical organoids. These molecular signatures open new avenues to examine how HNRNPH2-associated RNA dysregulation evolves across developmental time and recurs across independent biological contexts, providing a foundation for further mechanistic studies of this rare neurodevelopmental disorder.
SN - 2296-4185
ER -