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Reciprocal, methylation-dependent binding of Zfp57 and Gzf1 safeguards Dlk1-Dio3 imprinting during developmental reprogramming.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Reciprocal, methylation-dependent binding of Zfp57 and Gzf1 safeguards Dlk1-Dio3 imprinting during developmental reprogramming.
Συγγραφείς: Toren A; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.; Sheba Medical Center, Ramat Gan, Israel., Hoffman L; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Miodownik I; Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel., Mayshar Y; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Ben-Yair R; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Orenbuch AH; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Rubinstein H; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Lifshitz A; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel., Stok Ranen R; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel., Wainstein A; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Sheban D; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Shlush L; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Tanay A; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel., Afek A; Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel., Stelzer Y; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. yonatan.stelzer@weizmann.ac.il.
Πηγή: Nature communications [Nat Commun] 2026 Sep 02; Vol. 17 (1). Date of Electronic Publication: 2026 Sep 02.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : Nature Pub. Group
Ιατρικοί όροι (MeSH): Iodide Peroxidase*/genetics , Iodide Peroxidase*/metabolism , Intercellular Signaling Peptides and Proteins*/genetics , Intercellular Signaling Peptides and Proteins*/metabolism , Cellular Reprogramming*/genetics , DNA-Binding Proteins*/metabolism , DNA-Binding Proteins*/genetics , Membrane Proteins*/genetics , Membrane Proteins*/metabolism , Transcription Factors*/metabolism , Transcription Factors*/genetics , Repressor Proteins*/metabolism , Repressor Proteins*/genetics , Genomic Imprinting* , DNA Methylation*, Calcium-Binding Proteins/genetics ; Oocytes/metabolism ; Animals ; Mice ; Gene Expression Regulation, Developmental ; Female ; Alleles ; Protein Binding
Περίληψη: Genomic imprinting secures parent-specific gene expression through differential DNA methylation at imprinted control regions (ICRs). However, how unmethylated alleles resist de novo methylation remains unclear. Using an allelic Dlk1-Dio3 ICR methylation reporter and genome-wide loss-of-function screening, we identify the zinc finger protein GZF1 that binds the unmethylated maternal ICR and protects it from de novo methylation via a regulatory element containing GZF1 and ZFP57 motifs that mediates mutually exclusive, methylation-dependent binding. Loss of either factor causes reciprocal imprinting failure: Gzf1 loss induces maternal allele methylation, H3K4me3 depletion, and silencing of maternal transcripts, whereas Zfp57 loss results in maternalization. Remarkably, GZF1 protects the unmethylated ICR from de novo methylation in both oocytes and embryos, and its loss leads to perinatal death consistent with paternalization of the maternal allele. Together, our findings establish a reciprocal mechanism that maintains parental epigenetic asymmetry across both imprint establishment and embryonic reprogramming.
(© 2026. The Author(s).)
Competing Interests: Competing interests: The authors declare no competing interests.
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Grant Information: 2824/24 Israel Science Foundation (ISF); ERC_CoG EmbryoCellEnsemble EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
Substance Nomenclature: EC 1.11.1.- (iodothyronine deiodinase type III)
EC 1.11.1.8 (Iodide Peroxidase)
0 (Calcium-Binding Proteins)
0 (Dlk1 protein, mouse)
0 (Zfp-57 protein, mouse)
0 (Intercellular Signaling Peptides and Proteins)
0 (DNA-Binding Proteins)
0 (Membrane Proteins)
0 (Transcription Factors)
0 (Repressor Proteins)
Entry Date(s): Date Created: 20260902 Date Completed: 20260902 Latest Revision: 20260905
Update Code: 20260905
PubMed Central ID: PMC13538652
DOI: 10.1038/s41467-026-76890-w
PMID: 42686776
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2041-1723
DOI:10.1038/s41467-026-76890-w