Transcriptional landscape of THAP9 across Oligodendrocyte developmental stages: molecular mechanisms and network analysis

Oligodendrocyte maturation and myelination are essential for neurodevelopment, and theirdysregulation results in numerous neurological disorders. While model organisms haveprovided insights into these processes, human-specific regulatory mechanisms remain poorlyunderstood. Our study investigates the role of THAP9, a Drosophila P-element transposasehomolog, in oligodendrocyte development. We analysed RNA-sequencing [1] and H3K27acChIP-sequencing data [1], which revealed significant upregulation of THAP9 (Figure 1a) duringoligodendrocyte maturation with H3K27ac enrichment, showing higher transcriptional activity inmature oligodendrocytes (MOs) compared to OPCs. Further co-expression analysis revealedthat THAP9 expression correlates with oligodendrocyte differentiation markers, including myelin-associated genes (MOG, MBP) and developmental regulators (PDGFRA, SOX5, SOX6,SOX11) (Figure 1b). Notably, THAP9 has no known mouse or zebrafish homologs, pointing topotential species-specific aspects of oligodendrocyte maturation. Transcriptomic analysiscomparing natural oligodendrocytes with those derived from reprogrammed fibroblasts [2]showed contrasting results. While THAP9 expression increases during native oligodendrocytematuration, it decreases in reprogrammed cells, mirroring MBP expression, a late-stage marker(Figure 2). This discrepancy between natural and reprogrammed cells suggests that currentreprogramming protocols may not fully replicate the normal developmental process. Our resultsidentify THAP9 as a novel human-specific regulator of oligodendrocyte maturation, emphasisingthe importance of studying species-specific factors in neurodevelopment. This work opens newavenues for understanding myelination disorders and highlights the need for human-specificmodels to bridge gaps in neurogenetic research.Glia, 2025 E249