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MeCP2 gene dosage-dependent neurodevelopmentally restricted defects arise by SWI/SNF-mediated aberrant activation of cell fate-determining bivalent genes [RNA-Seq]

GSE299954 Homo sapiens (human) RNA-seq (gene expression) 18 samples Submitted 2026/01/20 Platform GPL24676
At a glance

RNA-seq (gene expression) · human · 18 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Homo sapiens (human)
Samples
18 samples: 6 × RNA-seq of human iPSC-derived NPCs, EGFP control, biol vs 6 × RNA-seq of human iPSC-derived NPCs, MECP2 overexpression, biol vs 3 × RNA-seq of human iPSC-derived neurons, EGFP control, biol vs 3 × RNA-seq of human iPSC-derived neurons, MECP2 overexpression, biolGroups 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
MeCP2 gene dosage-dependent neurodevelopmentally restricted defects arise by aberrant activation of cell fate-determining bivalent genesNature communications · 2026
Summary (written by the submitters)
Increased dosage of genes encoding for chromatin factors is thought to inevitably alter gene transcriptional output, leading to cellular dysfunctions. However, a mechanistic understanding of the molecular processes in action and their consistency across different cell types is still lacking. A prototypical gene in this context is MECP2, as its overexpression determines severe neurological deficits in MECP2 duplication syndrome (MDS) and its dosage is considered a crucial safety risk factor in gene therapy for Rett syndrome (RTT).
Read the full summary ↓
However, in MDS patients, MECP2 dysregulation arises at the embryonic stage while in RTT gene therapy, MECP2 is delivered into the mature brain. Despite these important implications, the molecular consequences of increased MECP2 gene dosage have yet to be fully elucidated. Surprisingly, we found that MeCP2 overexpression induced profound transcriptional alterations in neural progenitor cells (NPCs) while it had minimal or no effects in both mouse and human neurons. Consequently, MeCP2 overexpression in NPCs, but not mature neurons, led to profound functional alterations. Mechanistically, we observed that both endogenous and overexpressed Mecp2 bind to the same CpG island repertoire. In NPCs, lower endogenous Mecp2 levels facilitated stronger deposition of the ectopic protein into CpG islands, driving the transcriptional activation of many developmental bivalent genes, deranging neuronal differentiation. We uncovered that this activation is mediated by the interaction with the SWI/SNF chromatin remodeling complex. Conversely, in neurons, where endogenous Mecp2 is highly expressed, ectopic protein expression leads to minimal CpG island binding and accelerate protein degradation. Our findings reveal that increased gene dosage-dependent effects are highly influenced by cell type, levels of proteins and their mechanisms of action. These results provide a framework to interpret the relationship between Mecp2 chromatin binding and transcriptional output and suggest that Mecp2 overexpression is expected to be well tolerated in gene therapy applications for RTT.
Published in
MeCP2 gene dosage-dependent neurodevelopmentally restricted defects arise by aberrant activation of cell fate-determining bivalent genes
Luoni M, Kubacki M, Giannelli SG et al. · Nature communications 2026 · PMID 42026056 · doi:10.1038/s41467-026-71432-w
This dataset
Open GSE299954 in finder → Find more human RNA-seq 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 GSE299954_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: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1277701 and SRA study SRP592746. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 42026056) ↗
Study design
6 × RNA-seq of human iPSC-derived NPCs, EGFP control, biol vs 6 × RNA-seq of human iPSC-derived NPCs, MECP2 overexpression, biol vs 3 × RNA-seq of human iPSC-derived neurons, EGFP control, biol vs 3 × RNA-seq of human iPSC-derived neurons, MECP2 overexpression, biol

Supports a case/control comparison: 9 samples read as cases, 9 as controls.

How we read this: 4 replicated groups read from 18 sample titles; they account for 18 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
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Metadata from NCBI GEO, cached and refreshed periodically — the NCBI page above is authoritative. Downloads link straight to NCBI/ENA; nothing is proxied through BioTransfer.