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REST deficiency and neurogenic-to-gliogenic shift in down syndrome human cerebral organoids.

Overview

Authors: Tan Huang1,2, Chong-Teik Lim2, Wei Li1, Sharida Fakurazi3, John O Mason4, Pike-See Cheah3, Yi Li1, King-Hwa Ling2,5,6,7
ORCID iDs: John O Mason
  1. Department of Neurosurgery, The Second Affiliated Hospital of Zunyi Medical University, Zunyi City, 563000 Guizhou Province China
  2. Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor Malaysia
  3. Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor Malaysia
  4. Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Hugh Robson Building, 15 George Square, Edinburgh, EH8 9XD UK
  5. Malaysian Research Institute on Ageing (MyAgeing®), Universiti Putra Malaysia, 43400 Serdang, Selangor Malaysia
  6. M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Selangor Malaysia
  7. Fakultas Kedokteran, Universitas Pembangunan Nasional “Veteran” Jakarta, Jakarta, Indonesia
Institutions: Universiti Putra Malaysia (Malaysia); Zunyi Medical University (China); University of Edinburgh (United Kingdom); Universitas Pembangunan Nasional Veteran Jakarta (Indonesia); Universiti Tunku Abdul Rahman (Malaysia)
Journal: Molecular brain, volume 19, issue 1, article 55
Dates: received 15 December 2025; accepted 11 May 2026; published online 16 May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s13041-026-01313-2 · PMID 42143345 · PMCID PMC13348641 · OpenAlex W7161414610
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), other condition (population), developmental (subfield)
Methods: Smoothing, state filtering, decompositions, Connectivity, Spectral & time-frequency
Keywords: Cerebral organoid, Down syndrome, hiPSC, Neurodevelopment, REST
MeSH: Cerebrum*, Down Syndrome*, Neurogenesis*, Neuroglia*, Organoids*, Repressor Proteins*, Gene Expression Profiling, Gene Regulatory Networks, Humans, Induced Pluripotent Stem Cells, RE1-Silencing Transcription Factor, RNA, Messenger, STAT3 Transcription Factor (* major topic)
Topic: Genomics and Chromatin Dynamics (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: Geran Putra Berimpak, Universiti Putra Malaysia (GPB/2024/9810200); Science and Technology Planning Project of Guizhou Province (Guizhou Department Combine Basics-ZK [2022] General 627)
Citations: not cited yet (Europe PMC); 42 references in the paper

Abstract

Down syndrome (DS) features impaired cortical neurogenesis and excess gliogenesis, yet the temporal regulatory events driving this imbalance remain unclear. Here, we combine multi-timepoint transcriptomic analyses from publicly available datasets, network modelling, and machine-learning prioritization, with validation in isogenic human iPSC-derived cerebral organoids, to identify a discrete pathogenic window at 90 days in vitro (DIV 90). Across five developmental stages, REST target genes were preferentially dysregulated in DS organoids. WGCNA revealed a DS-associated module at DIV-90 that strongly overlapped with REST targets, and two orthogonal machine-learning approaches converged on six REST-regulated hub genes—CSTB, MCM3AP, PFKL, POFUT2, PRMT2, and RWDD2B. In trisomic organoids, REST mRNA and nuclear protein were markedly reduced at DIV-90, accompanied by diminished DCX expression and activation of NFIA and STAT3, suggesting a neurogenic-to-gliogenic fate transition. These findings suggest REST dysfunction as a potential temporal regulator of lineage imbalance in DS and highlight REST-linked networks as potential targets for early developmental intervention.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13041-026-01313-2.

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

Code

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Data

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Other data links

Data availability

The original contributions presented in the study are included in the article/Supplementary material; further inquiries can be directed to the corresponding author. All data sets used in this study are publicly available on the Gene Expression Omnibus (GEO) and the Sequence Read Archive (SRA). The accession numbers are GSE124513 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE124513), GSE208440 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE208440), GSE222365 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE222365), and PRJNA721827 (SRR14244005-SRR14244010).

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, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 8 authors, 5 keywords, 13 MeSH terms, 2 funders, 42 references.

Cite

This paper

Huang, T., Lim, C.-T., Li, W., Fakurazi, S., Mason, J. O., Cheah, P.-S., Li, Y., & Ling, K.-H. (2026). REST deficiency and neurogenic-to-gliogenic shift in down syndrome human cerebral organoids. Molecular brain, 19(1), 55. https://doi.org/10.1186/s13041-026-01313-2

BibTeX

@article{huang2026rest,
author = {Huang, Tan and Lim, Chong-Teik and Li, Wei and Fakurazi, Sharida and Mason, John O and Cheah, Pike-See and Li, Yi and Ling, King-Hwa},
title = {{REST deficiency and neurogenic-to-gliogenic shift in down syndrome human cerebral organoids}},
journal = {Molecular brain},
year = {2026},
month = may,
volume = {19},
number = {1},
pages = {55},
publisher = {BMC},
issn = {1756-6606},
doi = {10.1186/s13041-026-01313-2},
url = {https://doi.org/10.1186/s13041-026-01313-2},
pmid = {42143345},
pmcid = {PMC13348641}
}

RIS

TY - JOUR
AU - Huang, Tan
AU - Lim, Chong-Teik
AU - Li, Wei
AU - Fakurazi, Sharida
AU - Mason, John O
AU - Cheah, Pike-See
AU - Li, Yi
AU - Ling, King-Hwa
TI - REST deficiency and neurogenic-to-gliogenic shift in down syndrome human cerebral organoids
T2 - Molecular brain
J2 - Mol Brain
PY - 2026
DA - 2026/05/16
VL - 19
IS - 1
SP - 55
SN - 1756-6606
PB - BMC
DO - 10.1186/s13041-026-01313-2
UR - https://doi.org/10.1186/s13041-026-01313-2
LA - en
ER -

CSL-JSON

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