Dual role of ZIC2 during neural induction: from priming transcription factor to enhancer activator.
Overview
- Institute of Biomedicine and Biotechnology of Cantabria, CSIC/Universidad de Cantabria, Santander, 39011, Spain
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, 50931, Germany
- Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, 51429, Germany
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, 69117, Germany
- European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, 69117, Germany
- Faculty of Biosciences, Collaboration for Joint PhD Degree between EMBL and Heidelberg University, Heidelberg, 69117, Germany
- IFOM ETS—the AIRC Institute of Molecular Oncology, Milan, 20139, Italy
- Department of Biomedicine, Aarhus University, Aarhus, 8000, Denmark
- Department of Biomedicine, University of Basel, Basel University Hospital, Basel, 4031, Switzerland
Abstract
Defects in ZIC2, a member of the Zinc Finger of the Cerebellum family of transcription factors (TFs), cause holoprosencephaly, a congenital brain malformation characterized by the defective cleavage of cerebral hemispheres. However, the gene regulatory network (GRN) controlled by ZIC2 during neural development remains largely unexplored. Here, we combined a mouse embryonic stem cell (mESC) in vitro differentiation model toward anterior neural progenitors with genome editing and genomic methods to elucidate the ZIC2 GRN. We found that ZIC2 is dispensable in mESC due to compensation by ZIC3. In contrast, during neural induction ZIC2 directly controls the expression of master regulators implicated in the patterning and morphogenesis of specific brain regions (e.g. midbrain and roof plate). Mechanistically, ZIC2 plays a dual role in neural differentiation: during pluripotency exit, ZIC2 binds de novo to distal enhancers and increases their chromatin accessibility; during neural induction, ZIC2 is essential for the activation of a subset of the previously primed enhancers, which in turn control the expression of neural patterning regulators and signalling pathways (i.e. WNT) that prevent premature neuronal differentiation. Therefore, by sequentially acting as a promiscuous priming TF and selective enhancer activator, ZIC2 canalizes pluripotent cells toward neural progenitors with rostro-dorsal identities.
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Data
Datasets cited
- genome.ucsc.edu/
s/ — at genome.ucsc.edu; found in “Data availability”mariamafau
Data availability
All the ChIP-seq, ATAC-seq, RNA-seq, and Multiome datasets generated in this project have been deposited at GEO under accession codes: GSE306563, GSE306566, GSE306567, and GSE306666. Genome browser session: https://
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Versions
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Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 10 MeSH terms, 3 funders, 167 references.
Cite
This paper
Mariner-Faulí, M., Sánchez-Gaya, V., Robert, S. M., Respuela, P., de la Cruz-Molina, S., Lobato-Moreno, S., Trovato, M., Prummel, K. D., Noh, K.-M., Zaugg, J. B., & Rada-Iglesias, Á. (2026). Dual role of ZIC2 during neural induction: from priming transcription factor to enhancer activator. Nucleic acids research, 54(8), gkag374. https://
BibTeX
@article{marinerfauli202
author = {Mariner-Faulí, María and Sánchez-Gaya, Víctor and Robert, Sarah Malika and Respuela, Patricia and de la Cruz-Molina, Sara and Lobato-Moreno, Sara and Trovato, Matteo and Prummel, Karin D and Noh, Kyung-Min and Zaugg, Judith B and Rada-Iglesias, Álvaro},
title = {{Dual role of ZIC2 during neural induction: from priming transcription factor to enhancer activator}},
journal = {Nucleic acids research},
year = {2026},
month = apr,
volume = {54},
number = {8},
pages = {gkag374},
publisher = {Oxford University Press},
issn = {0305-1048},
doi = {10.1093/
url = {https://
pmid = {42033229},
pmcid = {PMC13109728}
}
RIS
TY - JOUR
AU - Mariner-Faulí, María
AU - Sánchez-Gaya, Víctor
AU - Robert, Sarah Malika
AU - Respuela, Patricia
AU - de la Cruz-Molina, Sara
AU - Lobato-Moreno, Sara
AU - Trovato, Matteo
AU - Prummel, Karin D
AU - Noh, Kyung-Min
AU - Zaugg, Judith B
AU - Rada-Iglesias, Álvaro
TI - Dual role of ZIC2 during neural induction: from priming transcription factor to enhancer activator
T2 - Nucleic acids research
J2 - Nucleic Acids Res
PY - 2026
DA - 2026/
VL - 54
IS - 8
SP - gkag374
SN - 0305-1048
PB - Oxford University Press
DO - 10.1093/
UR - https://
LA - en
ER -
CSL-JSON
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