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Enhancer poising enables pathogenic gene activation by noncoding variants [ATAC-seq]

GSE299694 Mus musculus (mouse) ChIP-seq / ATAC-seq (genome binding and open chromatin) 12 samples Submitted 2025/06/20 Platform GPL24247Platform GPL34328
At a glance

ChIP-seq / ATAC-seq (genome binding and open chromatin) · mouse · 12 samples

What it is
ChIP-seq / ATAC-seq (genome binding and open chromatin)Where proteins bind the genome, or which regions are open and active.
Organism
Mus musculus (mouse)
Samples
12 samples: 6 conditions, mostly in duplicateGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
Enhancer Poising Enables Pathogenic Gene Activation by Noncoding VariantsbioRxiv : the preprint server for biology · 2025
Summary (written by the submitters)
Single nucleotide variants within enhancers—non-coding DNA elements that regulate transcription—often lead to aberrant gene activation and contribute to a wide range of genetic disorders (Claussnitzer et al. 2015; Doan et al. 2016; Turner et al. 2017; Yanchus et al. 2022; Lettice et al. 2008). The mechanism by which ectopic gene activation occurs through these gain-of-function enhancer mutations remains poorly understood.
Read the full summary ↓
Using the ZRS, a benchmark disease-associated enhancer of Sonic hedgehog (Shh), as a model, we demonstrate that poised (i.e., accessible but inactive) chromatin sensitizes Shh to aberrant activation in anterior limb bud, leading to polydactyly. In the anterior limb cells of wild-type mice, Shh is inactive, but the ZRS is accessible and marked by enhancer-associated histone modifications. We demonstrate that this poising signature explains how over 20 independent rare variants within the ZRS cause Shh misexpression in the same anterior limb bud cell population, resulting in similar limb malformations, despite affecting binding sites for different activators and repressors. Disabling pioneer transcription factor binding to the ZRS suppresses its poised state in anterior cells, prevents aberrant activation of the ZRS by rare variants, and fully rescues limb malformations in variant knock-in mice. A thorough examination of other disease-associated enhancers with pathogenic gain-of-function variants revealed that they are all poised in tissues with ectopic activity. We use this poising signature to predict and validate in vivo ectopic forebrain activity of previously uncharacterized autism-associated non-coding variants. Our findings suggest that spatial enhancer poising, likely a byproduct of development, leads to susceptibility to non-coding mutations offering a potential mechanistic explanation for the burden of disease-associated non-coding variants.
Published in
Enhancer Poising Enables Pathogenic Gene Activation by Noncoding Variants
Hollingsworth EW, Chen Z, Chen CX et al. · bioRxiv : the preprint server for biology 2025 · PMID 40667262 · doi:10.1101/2025.06.20.660819
This dataset
Open GSE299694 in finder → Find more mouse ChIP / ATAC / CUT&Tag datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE299694_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: Look for peak files (.bed, .narrowPeak) and signal tracks (.bigWig) among the supplementary files; the raw reads are on ENA.

Also filed as BioProject PRJNA1276083 and SRA study SRP592063. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 40667262) ↗
Study design
6 conditions, mostly in duplicate
Anterior hindlimb, wild-type-hZRS404G>A, ATAC, ×2 Central hindlimb, wild-type-hZRS404G>A, ATAC, ×2 Posterior hindlimb, wild-type-hZRS404G>A, ATA… ×2 Anterior hindlimb, mZRS446T>AZIC-hZRS446T>A, … ×2 Central hindlimb, mZRS446T>AZIC-hZRS446T>A, A… ×2 Posterior hindlimb, mZRS446T>AZIC-hZRS446T>A,… ×2

Supports a between-group comparison across 12 samples.

How we read this: 6 replicated groups read from 12 sample titles; they account for 12 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
Datasets on a similar topic

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