A Mediator-dependent hypertranscriptional program governs neural stem cell fate decisions in vivo

Abstract

Hypertranscription, a global increase in transcriptional output, is a defining feature of stem cells, but its biological relevance and regulation in vivo remain unclear. Using Drosophila neural stem cells (neuroblasts), we investigate the function and regulation of hypertranscription. Neuroblasts exhibit higher transcriptional activity than their differentiated progeny, establishing them as a model of hypertranscriptional stem cells. We identify the Mediator complex as a key regulator of this elevated transcriptional state. Mediator is broadly enriched across neuroblast chromatin, and its depletion causes a substantial, selective reduction in transcription in neuroblasts, with only mild effects in differentiated cells. Functionally, Mediator depletion impairs lineage progression, causing an accumulation of undifferentiated, stem-like cells, highlighting the necessity of hypertranscription for proper stem cell fate and differentiation. Finally, we show that Drosophila brain tumor neuroblasts exhibit an exaggerated, Mediator-dependent hypertranscriptional program. These findings establish Mediator as a central regulator of hypertranscription in both normal and tumorigenic neural stem cells, crucial for neural differentiation and stem cell fate progression.