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Reciprocal, methylation-dependent binding of Zfp57 and Gzf1 safeguards Dlk1-Dio3 imprinting during developmental reprogramming [bulk RNAseq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE337302 | GEO | 2026/08/09

REPOSITORIES: GEO

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

Project description: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.

2026-08-04 | PXD080456 | Pride

Reciprocal, methylation-dependent binding of Zfp57 and Gzf1 safeguards Dlk1-Dio3 imprinting during developmental reprogramming [CUT&Tag]

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Reciprocal, methylation-dependent binding of Zfp57 and Gzf1 safeguards Dlk1-Dio3 imprinting during developmental reprogramming [ChIP-seq]

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

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Reciprocal, methylation-dependent binding of Zfp57 and Gzf1 safeguards Dlk1-Dio3 imprinting during developmental reprogramming [GZF1]

Project description:Genomic imprinting secures parent-specific gene expression through differential DNA methylation at imprinted control regions (ICRs). However, how unmethylated imprinted alleles resist de novo methylation remains unclear. Using an allelic methylation reporter at the Dlk1-Dio3 ICR and a genome-wide loss-of-function screen, we identify that the zinc finger protein GZF1 specifically binds the unmethylated maternal ICR and protects it from de novo methylation in mouse embryonic stem cells, early development, and oocytes. We further show that this protection occurs independently of Tet-mediated demethylation. A regulatory element containing GZF1 and ZFP57 motifs 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 erases paternal methylation, causing locus maternalization. Gzf1-null mice exhibit postnatal growth retardation, contextualizing cis-deletions of this region and illustrating how imprinting phenotypes may differ when studied through epigenetic perturbation versus genetic deletion. Together, our findings define a reciprocal mechanism by which sequence- and methylation-sensitive factors actively memorize parental epigenetic asymmetry through opposing waves of developmental reprogramming.

2026-08-09 | GSE324182 | GEO

Reciprocal, methylation-dependent binding of Zfp57 and Gzf1 safeguards Dlk1-Dio3 imprinting during developmental reprogramming [GZF1_snp]

Project description:Genomic imprinting secures parent-specific gene expression through differential DNA methylation at imprinted control regions (ICRs). However, how unmethylated imprinted alleles resist de novo methylation remains unclear. Using an allelic methylation reporter at the Dlk1-Dio3 ICR and a genome-wide loss-of-function screen, we identify that the zinc finger protein GZF1 specifically binds the unmethylated maternal ICR and protects it from de novo methylation in mouse embryonic stem cells, early development, and oocytes. We further show that this protection occurs independently of Tet-mediated demethylation. A regulatory element containing GZF1 and ZFP57 motifs 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 erases paternal methylation, causing locus maternalization. Gzf1-null mice exhibit postnatal growth retardation, contextualizing cis-deletions of this region and illustrating how imprinting phenotypes may differ when studied through epigenetic perturbation versus genetic deletion. Together, our findings define a reciprocal mechanism by which sequence- and methylation-sensitive factors actively memorize parental epigenetic asymmetry through opposing waves of developmental reprogramming.

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An Nlrp5-null mutation leads to attenuated de novo methylation in oocytes, accompanied by significant reduction in DNMT3L

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2025-12-22 | PXD056859 | Pride

De novo DNA methylation at imprinted loci during reprogramming into naïve and primed pluripotency

Project description:CpG islands (CGIs) including those at imprinting control regions (ICRs) are protected from de novo methylation in somatic cells. However, many cancers often exhibit CGI hypermethylation, implying that the machinery is impaired in cancer cells. Here, we conducted a comprehensive analysis of CGI methylation during the somatic cell reprogramming. Although most CGIs remain hypomethylated, a small subset of CGIs, particularly at several ICRs, were often de novo methylated in reprogrammed pluripotent stem cells (PSCs). Such de novo ICR methylation was linked with the silencing of reprogramming factors, which occurs at a late stage of reprogramming. The ICR-preferred CGI hypermethylation was similarly observed in human PSCs. Mechanistically, ablation of Dnmt3a prevented PSCs from de novo ICR methylation. Notably, the ICR-preferred CGI hypermethylation was observed in pediatric cancers, while adult cancers exhibit genome-wide CGI hypermethylation. These results may have important implications in the pathogenesis of pediatric cancers and the application of PSCs.

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DNA sequence determines epigenetic bistability at imprinting control regions [WGBS]

Project description:Genomic imprinting is regulated by parental-specific epigenetic marks that differentiate between maternal and paternal chromosomes. Despite identical DNA sequence, the presence or absence of DNA methylation leads to the establishment of two distinct epigenetic states at Imprinting Control Regions (ICR). Here we combine targeted epigenome engineering to generate ectopic loci in the mouse embryonic stem cell genome that recapitulate the epigenetic properties of ICRs. We describe these ectopic ICRs as strong cis-regulatory sequences that can adopt and memorise one of two opposing epigenetic states, dependent of pre-imposed DNA methylation. This bistability is unique to ICRs and enabled us to systematically study the genetic and epigenetic determinants required for creating and maintaining the observed states. Through sequence manipulation we show that the ICR DNA sequence confers autonomy of ICRs and is required for creating epigenetic bistability. Genetic screens using DNA-methylation-sensitive reporters identify key components involved in regulating maintenance of epigenetic states. Besides DNMT1, UHRF1 and ZFP57, we identify novel factors that prevent switching between methylated and unmethylated states and validate two of these candidates, ATF7IP and ZMYM2, to be important for epigenetic memory at ICRs. In summary we show that the DNA sequence of ICRs provides the prerequisite for establishment of two distinct epigenetic states, while DNA and histone modifications ensure their stable propagation.

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