Coordinated regulation of 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 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) binds cis-regulatory elements of most genes uniquely transcribed in neuroblasts. Loss of fruC function alone has no effect on INP commitment but drives INP dedifferentiation when translational control is reduced. FruC negatively regulates gene expression by promoting low-level enrichment of the repressive histone mark H3K27me3 in gene cis-regulatory regions. Identical to fruC loss-of-function, reducing Polycomb Repressive Complex 2 activity increases stemness gene activity. We propose low-level H3K27me3 enrichment fine-tunes gene transcription in stem cells, a mechanism likely conserved from flies to humans.
Sequencing data have been deposited in GEO under accession codes GSE218257All quantifications are provided in Supplementary File 1.All analysis code used has been deposited in GitHub: https://github.com/Cheng-Yu-Lee-Lab/Rajan-et-al-2023
Low-level repressive histone marks fine-tune stemness gene transcription in neural stem cellsNCBI Gene Expression Omnibus, GSE218257.
The molecular landscape of neural differentiation inthe developing Drosophila brain revealed by targeted scRNA-seq and multi-informatic analysisNCBI Gene Expression Omnibus, GSE153723.
Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions in DrosophilaNCBI Gene Expression Omnibus, GSE150931.
- Cheng-Yu Lee
- Melissa M Harrison
- Cheng-Yu Lee
- Stephen F Goodwin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Chris Q Doe, Howard Hughes Medical Institute, University of Oregon, United States
© 2023, Rajan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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