Srr2-dependent SOX2 levels govern the chromatin and transcriptional landscape of adult neural stem cell fate decisions in mouse.

Overview

1. Cellular Oncology Group, Biogipuzkoa Health Research Institute,Paseo Dr. Beguiristain S/N, San Sebastian, 20014 Spain
2. Departamento de Biología Celular y Biología Funcional & Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia,Burjassot, Spain
3. Instituto de Biomedicina de Valencia (IBV-CSIC),Valencia, Spain
4. Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED),Madrid, Spain
5. Present address: Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania,Philadelphia, PA USA
6. Laboratory of Stem Cell Biology and Developmental Genetics, The Francis Crick Institute,1 Midland Road, London, NW1 1AT UK
7. IKERBASQUE, Basque Foundation for Science,Bilbao, Spain
8. Centro de Investigación Biomédica en Red Sobre Fragilidad y Envejecimiento (CIBERFES),Madrid, Spain

Abstract

Background: Stem cell maintenance and lineage commitment in the nervous system require precise regulation of transcription factors, with SOX2 serving as a pivotal regulator. SOX2 expression is controlled by multiple enhancers, including the Sox2 regulatory region 2 (Srr2). However, the specific role of Srr2 in adult neurogenesis and chromatin regulation during neural lineage commitment remains incompletely understood.

Results: To dissect the function of Srr2, we generate a CRISPR-Cas9 mouse model harboring a targeted deletion of this enhancer. Srr2 deletion reduce SOX2 levels in proliferating, but not differentiating, neurosphere cultures, while impairing both neuronal and oligodendroglial differentiation. Paired bulk RNA-seq and ATAC-seq during proliferation and early differentiation reveal that loss of Srr2 induces widespread chromatin compaction during proliferation, which partially converges toward wild-type states upon early differentiation. Multi-omic integration identifies a subset of neurogenic genes exhibiting persistent promoter closure and impaired transcriptional induction in proliferating mutant cells, despite being normally translated during neural differentiation. In vivo, subependymal zone cells of Srr2del/del mice exhibit lower SOX2 and FOXG1 expression, fewer ASCL1/OLIG2 progenitors, and reduced neuronal and oligodendroglial marker expression.

Conclusions: These findings establish Srr2 as a critical enhancer of Sox2 required to maintain a chromatin environment permissive for neural differentiation during stem cell proliferation. Our study underscores the essential role of non-coding regulatory elements in coordinating chromatin accessibility, transcriptional programs, and stem cell fate decisions during adult neurogenesis.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13059-026-04126-7.

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

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

• figshare:32798307, at figshare; found in DataCite
• geo:GSE319463, at NCBI GEO; found in the references
• zenodo:20142987, at Zenodo; found in “Availability of data and materials”

Availability of data and materials

RNA-seq data generated in this study have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE319463 [59] for Srr2del/del samples and GSE196329 [60] for WT samples. ATAC-seq data have been deposited in GEO under accession number GSE319464 [61] for Srr2del/del samples and GSE196329 [60] for WT samples. Fluorescence microscopy images used for quantification in Fig. 1, Fig. 4 and Fig. S1–S2 have been deposited in Zenodo (https://zenodo.org/records/20142987) [62].

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

Data availability

No datasets were generated or analysed during the current study.

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, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 13 MeSH terms, 7 funders, 59 references.

Cite

This paper

Cruces-Salguero, S., Jordán-Pla, A., Domingo-Muelas, A., Morante-Redolat, J. M., Rizzoti, K., Matheu, A., Fariñas, I., Lovell-Badge, R., & Moncho-Amor, V. (2026). Srr2-dependent SOX2 levels govern the chromatin and transcriptional landscape of adult neural stem cell fate decisions in mouse. Genome biology, 27(1), 208. https://doi.org/10.1186/s13059-026-04126-7

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1155/humu/4225263

The Charcot-Marie-Tooth Neuropathy (CMTX3) Complex Structural Variation Causes Differential SOX3 Spatiotemporal Expression.

Journal: Human mutation

In common: genetics / omics, 6 references

[2] doi:10.1016/j.isci.2026.117332

The <i>Sox2</i> regulatory region 42 produces enhancer RNAs that influence neuronal migration during cortical development.

Journal: iScience

In common: genetics / omics, mouse, 4 references

[3] doi:10.1126/sciadv.aeh9771 [code]

Lipidomic profiling reveals age-dependent changes in plasma membrane lipids that affect neural stem cell aging.

Journal: Science advances

In common: genetics / omics, mouse, 3 references

[4] doi:10.1038/s41467-026-74058-0

IQGAP3 bridges matrix stiffness with glioma stem cell maintenance and radioresistance by stabilizing SOX2.

Journal: Nature communications

In common: mouse, 3 references

[5] doi:10.1038/s41467-026-70478-0 [code]

Jagged-mediated lateral induction patterns Notch3 signaling within adult neural stem cell populations.

Journal: Nature communications

In common: 3 references

[6] doi:10.1038/s44318-026-00768-2 [code]

The H3K36me3 methyltransferase SETD2 contributes to PAF1C interactions with RNA Pol II and is required for neuronal differentiation.

Journal: The EMBO journal

In common: mouse, 2 references

[7] doi:10.1210/endrev/bnag008

Diverse SOX3 genetic variants and their associated phenotypic spectrum in human disease.

Journal: Endocrine reviews

In common: genetics / omics, 2 references

[8] doi:10.1038/s41586-026-10832-w [code]

Subnuclear genome compartmentalization controls bivalent chromatin activity.

Journal: Nature

In common: 2 references

[9] doi:10.1039/d5dd00190k [code]

Identification of drug candidates against glioblastoma with machine learning and high-throughput screening of heterogeneous cellular models.

Journal: Digital discovery

In common: 2 references

[10] doi:10.1186/s13059-026-04050-w

Transposable element-mediated evolutionary expansion of Sox2- and Brn2-binding regulatory modules for mammalian neural-cell differentiation.

Journal: Genome biology

In common: 2 references

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.