Low-level repressive histone marks fine-tune stemness gene transcription in neural stem cells

Coordinated regulation of stemness gene activity by transcriptional and translational mechanisms poise stem cells for a timely cell-state transition during differentiation. Although important for all stemness-to-differentiation transitions, mechanistic understanding of the fine-tuning of stemness gene transcription is lacking due to the compensatory effect of translational control. We used intermediate neural progenitor (INP) identity commitment to define the mechanisms that fine-tune stemness gene transcription in fly neural stem cells (neuroblasts). We demonstrate that the transcription factor Fruitless^C(Fru^C) bindscis-regulatory elements of most genes uniquely transcribed in neuroblasts. Loss offru^Cfunction alone has no effect on INP commitment but drives INP dedifferentiation when translational control is reduced. Fru^Cnegatively regulates gene expression by promoting low-level enrichment of the repressive histone mark H3K27me3 in genecis-regulatory regions. Identical tofru^Closs-of-function, reducing Polycomb Repressive Complex 2 activity increases stemness gene activity. We propose low-level H3K27me3 enrichment fine-tunes stemness gene transcription in stem cells, a mechanism likely conserved from flies to humans.