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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- Developmental Biology
- Stem Cells and Regenerative Medicine
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We present evidence implicating the BAF (BRG1/BRM Associated Factor) chromatin remodeler in meiotic sex chromosome inactivation (MSCI). By immunofluorescence (IF), the putative BAF DNA binding subunit, ARID1A (AT-rich Interaction Domain 1 a), appeared enriched on the male sex chromosomes during diplonema of meiosis I. Germ cells showing a Cre-induced loss of ARID1A arrested in pachynema and failed to repress sex-linked genes, indicating a defective MSCI. Mutant sex chromosomes displayed an abnormal presence of elongating RNA polymerase II coupled with an overall increase in chromatin accessibility detectable by ATAC-seq. We identified a role for ARID1A in promoting the preferential enrichment of the histone variant, H3.3, on the sex chromosomes, a known hallmark of MSCI. Without ARID1A, the sex chromosomes appeared depleted of H3.3 at levels resembling autosomes. Higher resolution analyses by CUT&RUN revealed shifts in sex-linked H3.3 associations from discrete intergenic sites and broader gene-body domains to promoters in response to the loss of ARID1A. Several sex-linked sites displayed ectopic H3.3 occupancy that did not co-localize with DMC1 (DNA meiotic recombinase 1). This observation suggests a requirement for ARID1A in DMC1 localization to the asynapsed sex chromatids. We conclude that ARID1A-directed H3.3 localization influences meiotic sex chromosome gene regulation and DNA repair.
