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MECP2 mutations rewire human ESC fate and bias cortical lineage commitment.

Overview

Authors: Marion Guillon1, Margaux Brin1, Elodie Gabet1, Justine Gromaire1, Mathéa Bernard1, Laetitia Laurent1, Théo Rabin1, Lisa Bianchin1, Marie Veziano1, Julie Kloda1, Alexia Bernard1, Laila Asali1, Yi Liu2,3, Anthony Flamier1,4
ORCID iDs: Yi Liu, Anthony Flamier
  1. Centre de recherche Azrieli du CHU Sainte-Justine, Montreal, QC, Canada
  2. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  3. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
  4. Department of Neurosciences, Université de Montréal, Montreal, QC, Canada
Institutions: CHU Sainte-Justine Research Center (Canada); Université de Montréal (Canada)
Journal: Stem cell reports, volume 21, issue 5, article 102895
Dates: received 23 February 2026; accepted 25 March 2026; published online 23 April 2026; in print May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.stemcr.2026.102895 · PMID 42030940 · PMCID PMC13163216 · OpenAlex W4414764101
Open access: gold, a free copy (OpenAlex)
Preprint: doi:10.1101/2025.09.30.679576
Status: code on request
Categories: genetics / omics (modality), human (organism), other condition (population)
Methods: Statistics, Smoothing, state filtering, decompositions, Machine learning, Preprocessing, Evoked potentials, Connectivity
Keywords: MECP2, Rett syndrome, pluripotency, EMX1, transcriptomics, neurodevelopment, cerebral organoids, lineage specification, stem cell differentiation
MeSH: Cell Lineage*, Cerebral Cortex*, Human Embryonic Stem Cells*, Methyl-CpG-Binding Protein 2*, Mutation*, Cell Differentiation, Gene Expression Regulation, Developmental, Homeodomain Proteins, Humans, Rett Syndrome, Transcription Factors, Transcriptome (* major topic)
Topic: CCD and CMOS Imaging Sensors (Electrical and Electronic Engineering, Engineering), according to OpenAlex
Funding: Canadian Institutes of Health Research; Stem Cell Network; Brain Canada Foundation
Citations: not cited yet (Europe PMC); 59 references in the paper
Research resources: Purified anti-Oct4 (Oct3) Antibody RRID:AB_2561767, Anti-GAPDH antibody EPR16891 RRID:AB_2630358, MAP2 (D5G1) Rabbit Monoclonal Antibody RRID:AB_2722660, Donkey Anti-Rabbit IgG H&L (HRP) RRID:AB_2904602, SAMtools RRID:SCR_002105, Fiji image processing package.76 RRID:SCR_002285, GraphPad Prism GraphPad Software V.10 RRID:SCR_002798, STAR RRID:SCR_004463, Trim Galore! RRID:SCR_011847, featureCounts RRID:SCR_012919, FASTQC RRID:SCR_014583, DESeq2 RRID:SCR_015687, RandomForest Package in R RRID:SCR_015718, Seurat V.5 RRID:SCR_016341, TensorFlow RRID:SCR_016345, clusterProfiler RRID:SCR_016884, Keras RRID:SCR_026159

Abstract

Rett syndrome arises from loss-of-function mutations in the X-linked chromatin regulator MECP2, yet the earliest molecular derailments in development are poorly defined. Using isogenic human embryonic stem cell (hESC) models carrying three patient-derived MECP2 mutations, we followed the transcriptome from pluripotency through neuroectoderm, neural stem/progenitor stages. Developmental stage dominated transcriptional variance, but mutants shared a secondary program enriched for synaptic-membrane and extracellular matrix genes. Single-cell/bulk profiling at the embryonic stem cell (ESC) stage revealed partial naïve-like drift, marked by the up-regulation of the naïve-enriched factor ZFP42/REX1 and related markers in MECP2-mutant lines. Among convergently dysregulated genes, the cortical determinant EMX1 showed an abnormal developmental trajectory, early repression followed by overshoot, and was consistently altered across independent Rett PSC models. Single-nucleus RNA-seq of cerebral organoids uncovered allele-specific yet convergent disturbances in cortical lineage allocation. These data chart a continuous developmental trajectory for MECP2-mutant cells and nominate naïve-like drift and mis-timed EMX1 expression as tractable entry points for dissecting Rett pathogenesis.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.

Data

Datasets cited

Data and code availability

Genomic data are available through a public repository (bulk RNAseq: GSE303838 (https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE303838); scRNAseq: GSE303813 (https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE303813); snRNAseq: GSE303977 (https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE303977)).

All other raw data and codes are available upon request to the lead contact.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 9 keywords, 12 MeSH terms, 3 funders, 59 references, 17 RRIDs.

Cite

This paper

Guillon, M., Brin, M., Gabet, E., Gromaire, J., Bernard, M., Laurent, L., Rabin, T., Bianchin, L., Veziano, M., Kloda, J., Bernard, A., Asali, L., Liu, Y., & Flamier, A. (2026). MECP2 mutations rewire human ESC fate and bias cortical lineage commitment. Stem cell reports, 21(5), 102895. https://doi.org/10.1016/j.stemcr.2026.102895

BibTeX

@article{guillon2026mecp2,
author = {Guillon, Marion and Brin, Margaux and Gabet, Elodie and Gromaire, Justine and Bernard, Mathéa and Laurent, Laetitia and Rabin, Théo and Bianchin, Lisa and Veziano, Marie and Kloda, Julie and Bernard, Alexia and Asali, Laila and Liu, Yi and Flamier, Anthony},
title = {{MECP2 mutations rewire human ESC fate and bias cortical lineage commitment}},
journal = {Stem cell reports},
year = {2026},
month = apr,
volume = {21},
number = {5},
pages = {102895},
publisher = {Elsevier},
issn = {2213-6711},
doi = {10.1016/j.stemcr.2026.102895},
url = {https://doi.org/10.1016/j.stemcr.2026.102895},
pmid = {42030940},
pmcid = {PMC13163216}
}

RIS

TY - JOUR
AU - Guillon, Marion
AU - Brin, Margaux
AU - Gabet, Elodie
AU - Gromaire, Justine
AU - Bernard, Mathéa
AU - Laurent, Laetitia
AU - Rabin, Théo
AU - Bianchin, Lisa
AU - Veziano, Marie
AU - Kloda, Julie
AU - Bernard, Alexia
AU - Asali, Laila
AU - Liu, Yi
AU - Flamier, Anthony
TI - MECP2 mutations rewire human ESC fate and bias cortical lineage commitment
T2 - Stem cell reports
J2 - Stem Cell Reports
PY - 2026
DA - 2026/04/23
VL - 21
IS - 5
SP - 102895
SN - 2213-6711
PB - Elsevier
DO - 10.1016/j.stemcr.2026.102895
UR - https://doi.org/10.1016/j.stemcr.2026.102895
LA - en
ER -

CSL-JSON

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