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MECP2 Mutations Rewire Human ESC Fate and Bias Cortical Lineage Commitment II

GSE303977 Homo sapiens Expression profiling by high throughput sequencing 8 samples Submitted 2026/04/23 Platform GPL34281
Summary
Rett syndrome arises from loss-of-function mutations in the X-linked chromatin regulator MECP2, yet the earliest molecular derailments in human development remain poorly defined. Using isogenic hESC models carrying three patient-derived MECP2 mutations, we followed the transcriptome from pluripotency through neuro-ectoderm, neural stem, and neural progenitor stages and into four-month cerebral organoids. Stage dominated transcriptional variance, but mutants shared a secondary program enriched for synaptic-membrane and extracellular-matrix genes. Single-cell profiling revealed a naïve-like, hyper-proliferative state marked by up-regulation of ZFP42 at ESC stage. Strikingly, EMX1, a cortical radial-glia determinant, was consistently suppressed from the earliest stage onward, and cerebral organoids subsequently generated fewer excitatory neurons in favour of inhibitory and glial lineages. These data chart a continuous developmental trajectory for MECP2-mutant human cells and nominate ZFP42 and EMX1 dysregulation as tractable entry points for dissecting Rett pathogenesis.
Published in
MECP2 mutations rewire human ESC fate and bias cortical lineage commitment
Guillon M, Brin M, Gabet E et al. · Stem cell reports 2026 · PMID 42030940 · doi:10.1016/j.stemcr.2026.102895
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Also filed as BioProject PRJNA1298343 and SRA study SRP604390. Searching any of these in the dataset finder brings you back here.

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