Integrated Transcriptomic Analysis of Human Neural Progenitor Cells Reveals Key Pathways and Therapeutic Targets in Fragile X Syndrome
TL;DR
It is shown that the structural and network deficits of FXS are genetically associated at the progenitor state due to altered epigenetic chromatin regulation, histone accumulation, and early synaptic targeting failure, demonstrating that the structural and network deficits of FXS are genetically associated at the progenitor state due to altered epigenetic chromatin regulation.
Abstract
Fragile X syndrome (FXS), caused by the silencing of the FMR1 gene, is characterized by synaptic defects in mature networks. This study aims to elucidate early transcriptomic abnormalities in human FXS neural progenitor cells (NPCs) to uncover pre-synaptic mechanisms of the disease. An integrated transcriptomic re-analysis of the human FXS NPC dataset GSE218676 was performed using the GEO2R platform. Differentially expressed genes (DEGs) were identified using strict statistical criteria (adjusted P -value < 0.05 and |log 2 fold change| ≥ 1.0). Downstream pathways and functional ontologies were mapped using the Enrichr platform across Kyoto Encyclopedia of Genes and Genomes (KEGG) 2026, Reactome 2024, WikiPathways 2024, BioPlanet 2019, and Gene Ontology (GO 2026) databases. A total of 66 highly stringent DEGs were identified (34 up-regulated and 32 down-regulated). FMR1 expression was severely abolished (log2 fold change = −7.25). Crucially, core histone-clustered genes, H3C3 and H2BC3 , exhibited profound up-regulation. Functional enrichment analyses mapped these transcriptomic changes to significant alterations in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor clustering (GO:0098966), post-transcriptional gene silencing, G-quadruplex RNA binding, and TP53 signaling pathways. These bioinformatic insights unveil a critical neurodevelopmental shift, demonstrating that the structural and network deficits of FXS are genetically associated at the progenitor state due to altered epigenetic chromatin regulation, histone accumulation, and early synaptic targeting failure.