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

Abstract

AbstractCoordinated 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 FruitlessC(FruC) bindscis-regulatory elements of most genes uniquely transcribed in neuroblasts. Loss offruCfunction alone has no effect on INP commitment but drives INP dedifferentiation when translational control is reduced. FruCnegatively regulates gene expression by promoting low-level enrichment of the repressive histone mark H3K27me3 in genecis-regulatory regions. Identical tofruCloss-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.