Histone H1 variants regulate neurodevelopmental transcriptional programs in autism with 16p11.2 deletion.
Overview
- Department of Human Genetics and Computational Medicine, Gray School of Medical Sciences, Tel Aviv University, Ramat Aviv, 6997801 Israel
- Biozentrum, University of Basel, Basel, Switzerland
Abstract
Background: Neurodevelopmental disorders, including autism spectrum disorder, involve widespread transcriptional dysregulation. Copy number variations at 16p11.2 are among the strongest genetic risk factors for autism spectrum disorder, yet the molecular mechanisms by which these copy number variations contribute to neurodevelopmental pathology remain unclear.
Results: We identify significant genetic associations between autism spectrum disorder susceptibility and the HIST1 histone gene cluster through genome-wide analysis. Transcriptomic profiling across post-mortem brain tissue, patient-derived neural progenitor cells, neurons, and cerebral organoids reveals consistent upregulation of linker histone variants H1.2 and H1.5 in idiopathic autism spectrum disorder and 16p11.2 hemi-deletion carriers, but not in schizophrenia or bipolar disorder. Functional assays demonstrate that dysregulated H1 expression disrupts gene networks involved in synaptic signaling, chromatin remodeling, and neural differentiation. Mechanistically, we link H1 upregulation to MAZ, a transcription factor encoded within the 16p11.2 locus. MAZ binds the promoter regions of H1 genes and represses their transcription. Knockdown of MAZ leads to H1 overexpression. H1 upregulation alone is sufficient to alter the expression of autism spectrum disorder-associated genes.
Conclusions: Our findings define a MAZ-dependent regulation of H1 dosage as a critical chromatin-mediated mechanism contributing to transcriptional pathology in 16p11.2-associated autism spectrum disorder.
Supplementary Information: The online version contains supplementary material available at 10.1186/
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE292323 — at NCBI GEO; found in “Data availability”
Data availability
The sequencing data generated in this study have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE292323 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 6 keywords, 13 MeSH terms, 2 funders, 70 references.
Cite
This paper
Brudno, R., Askayo, D., Khair, D., Shayevitch, R., Keydar, I., Zmudjak-Olevson, M., Lev-Maor, G., Zavolan, M., Elkon, R., & Ast, G. (2026). Histone H1 variants regulate neurodevelopmental transcriptional programs in autism with 16p11.2 deletion. Genome biology, 27(1), 225. https://
BibTeX
@article{brudno2026histo
author = {Brudno, Roni and Askayo, Dan and Khair, Doha and Shayevitch, Ronna and Keydar, Ifat and Zmudjak-Olevson, Michal and Lev-Maor, Galit and Zavolan, Mihaela and Elkon, Ran and Ast, Gil},
title = {{Histone H1 variants regulate neurodevelopmental transcriptional programs in autism with 16p11.2 deletion}},
journal = {Genome biology},
year = {2026},
month = may,
volume = {27},
number = {1},
pages = {225},
publisher = {BMC},
issn = {1474-7596},
doi = {10.1186/
url = {https://
pmid = {42169156},
pmcid = {PMC13366670}
}
RIS
TY - JOUR
AU - Brudno, Roni
AU - Askayo, Dan
AU - Khair, Doha
AU - Shayevitch, Ronna
AU - Keydar, Ifat
AU - Zmudjak-Olevson, Michal
AU - Lev-Maor, Galit
AU - Zavolan, Mihaela
AU - Elkon, Ran
AU - Ast, Gil
TI - Histone H1 variants regulate neurodevelopmental transcriptional programs in autism with 16p11.2 deletion
T2 - Genome biology
J2 - Genome Biol
PY - 2026
DA - 2026/
VL - 27
IS - 1
SP - 225
SN - 1474-7596
PB - BMC
DO - 10.1186/
UR - https://
LA - en
ER -
CSL-JSON
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