Low-level repressive histone marks fine-tune gene transcription in neural stem cells
- University of Michigan-Ann Arbor, United States
- University of Oxford, United Kingdom
- University of Wisconsin-Madison, United States
Abstract
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.
Data availability
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
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Low-level repressive histone marks fine-tune stemness gene transcription in neural stem cellsNCBI Gene Expression Omnibus, GSE218257.
Article and author information
Author details
Melissa M Harrison
Funding
National Institute of Neurological Disorders and Stroke (R01NS107496)
- Cheng-Yu Lee
National Institute of Neurological Disorders and Stroke (R01NS111647)
- Melissa M Harrison
- Cheng-Yu Lee
Wellcome Trust (106189/Z/14/Z)
- Stephen F Goodwin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 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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Low-level repressive histone marks fine-tune gene transcription in neural stem cells
eLife 12:e86127.
https://doi.org/10.7554/eLife.86127
Further reading
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During the first lineage segregation, mammalian embryos generate the inner cell mass (ICM) and trophectoderm (TE). ICM gives rise to the epiblast (EPI) that forms all cell types of the body, an ability referred to as pluripotency. The molecular mechanisms that induce pluripotency in embryos remain incompletely elucidated. Using knockout (KO) mouse models in conjunction with low-input ATAC-seq and RNA-seq, we found that Oct4 and Sox2 gradually come into play in the early ICM, coinciding with the initiation of Sox2 expression. Oct4 and Sox2 activate the pluripotency-related genes through the putative OCT-SOX enhancers in the early ICM. Furthermore, we observed a substantial reorganization of chromatin landscape and transcriptome from the morula to the early ICM stages, which was partially driven by Oct4 and Sox2, highlighting their pivotal role in promoting the developmental trajectory toward the ICM. Our study provides new insights into the establishment of the pluripotency network in mouse preimplantation embryos.
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