GEO series

Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [ATAC-Seq]

GSE298001 Mus musculus Genome binding/occupancy profiling by high throughput sequencing 36 samples Submitted 2025/11/28 Platform GPL24247

Summary

Neural progenitor cells exhibit developmental plasticity, as they are able to commit to different developmental trajectories in response to external stimuli. How these decisions are stabilized at the molecular level remains a highly active area of research. One way to stably integrate external stimuli into cell fate decisions is through epigenetic marks. H4K16ac represents a unique epigenetic mark, as it modulates chromatin compaction and is the only known active histone modification that is transmitted intergenerationally. The deposition of H4K16ac is mediated by the evolutionarily conserved MSL acetyltransferase complex (MSLc), via its catalytic subunit MOF, and mutations in its components have been linked to neurodevelopmental disorders. To dissect the role of the MSLc, we employed a multi-pronged strategy combining both chronic and acute depletion models. Deletion of the MSLc structural backbone Msl1 in vivo resulted in embryonic lethality by E10, and single-cell multi-omics analysis revealed a systemic disruption in lineage commitment within the neuroectoderm. To distinguish primary molecular functions from secondary developmental consequences, we complemented this with a rapid degradation system in vitro, coupled to directed differentiation into two distinct neural lineages. We found that the MSLc facilitates accessibility at regulatory elements in the early stages of lineage commitment during neurogenesis. We observe a significant decrease in enhancer-promoter contacts in a specific subset of neurodevelopmental genes. In the absence of MSLc this gene group fails to reach adequate gene expression levels upon differentiation, resulting in abnormal morphology. Intriguingly, MSLc loss later on during differentiation does not phenocopy this. Our work reveals MSLc-mediated gene priming as a crucial mechanism potentiating the transcriptional activation of neurodevelopmental gene programs. Our study describes a new mode of epigenetic regulation which cements initial cell fate decisions and provides molecular insights into MSLc-associated developmental disorders.

Published in

Stage-specific epigenetic priming amplifies gene activation during lineage commitment

Foertsch A, Hirsch N, Seyfferth J et al. · Science advances 2026 · PMID 41894493 · doi:10.1126/sciadv.adz8889

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Direct links to NCBI, no account and no request form: the whole study as GSE298001_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 36 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1267099 and SRA study SRP587387. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 41894493) ↗

Study design

10 conditions, mostly with about 4 replicates each

ATAC, NPC, MSL1-F, ×4 ATAC, NPC, MSL1-F KO, ×4 ATAC, Day7 Neuron, MSL1-F, ×4 ATAC, Day7 Neuron, MSL1-F KO, ×4 ATAC, Day14 Neuron, MSL1-F, ×4 ATAC, Day14 Neuron, MSL1-F KO, ×4 ATAC, Day7 Neuron, MSL1-AID ctrl, ×4 ATAC, NPC, MSL1-AID ctrl, ×3 +2 more

Supports a case/control comparison: 5 samples read as cases, 7 as controls.

10 replicated groups read from 36 sample titles; they account for 36 of them. Check it against the sample list below before relying on it.

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