ZNF445 is a primary regulator of genomic imprinting
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE115387 | GEO | 2019/01/11
REPOSITORIES: GEO
Similar Datasets
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.
2022-07-20 | GSE203404 | GEO
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.
2022-07-20 | GSE176460 | GEO
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.
2022-07-20 | GSE176459 | GEO
Project description:Genomic imprinting is controlled by CpG-rich regions (ICRs) acquiring differential methylation in the female and male germline and maintaining it in a parental origin-specific manner in somatic cells. Despite their expected mutation rate due to spontaneous deamination of methylated cytosines, ICRs maintain their CpG-richness and show conservation of CpG-bearing transcription binding sites in mammals. In order to gain further insights into the mechanisms of maintenance of methyl CpGs, we sought to identify the proteins interacting with the methylated allele of the ICRs, by determining the interactors of ZFP57 that recognizes a specific methylated ICR motif in mouse ESCs. Several proteins including factors involved in mRNA processing/splicing, chromatin organization, transcription and DNA repair were identified through a tagged approach coupled to LC–MS/MS analysis. The demonstration of the components of the post-replicative mismatch-repair (MMR) complex as ZFP57 interactors prompted us to investigate the DNA binding profile of MSH2 and MSH6 by chromatin immunoprecipitation and sequencing. We found that these proteins were enriched at the methylated allele of the ICRs and their binding was mediated by the ZFP57/KAP1 complex, suggesting that the MMR complex is recruited to these loci to preserve their genetic integrity.
2022-08-16 | GSE205042 | GEO
Project description:Genomic imprinting is controlled by CpG-rich regions (ICRs) acquiring differential methylation in the female and male germline and maintaining it in a parental origin-specific manner in somatic cells. Despite their expected mutation rate due to spontaneous deamination of methylated cytosines, ICRs maintain their CpG-richness and show conservation of CpG-bearing transcription binding sites in mammals. In order to gain further insights into the mechanisms of maintenance of methyl CpGs, we sought to identify the proteins interacting with the methylated allele of the ICRs, by determining the interactors of ZFP57 that recognizes a specific methylated ICR motif in mouse ESCs. Several proteins including factors involved in mRNA processing/splicing, chromatin organization, transcription and DNA repair were identified through a tagged approach coupled to LC–MS/MS analysis. The demonstration of the components of the post-replicative mismatch-repair (MMR) complex as ZFP57 interactors prompted us to investigate the DNA binding profile of MSH2 and MSH6 by chromatin immunoprecipitation and sequencing. We found that these proteins were enriched at the methylated allele of the ICRs and their binding was mediated by the ZFP57/KAP1 complex, suggesting that the MMR complex is recruited to these loci to preserve their genetic integrity.
2022-08-16 | GSE205041 | GEO
Project description:DNA methylation is essential for embryonic development and implicated in the regulation of genomic imprinting. Genomic imprinting is established in the germline through parent-specific methylation of distinct cis-regulatory DNA sequences, called imprinting control regions (ICRs). Which factors bind to the opposing chromatin states at ICRs within the same nuclear environment was not systematically addressed. By using a proximity labelling approach with the methylation sensitive transcription factor ZFP57, we identified ATF7IP and other major components of the epigenetic maintenance machinery at ICRs.
2023-03-10 | PXD034918 | Pride
Project description:We report that SMAD1/5 bind the ICRs by interacting with the ZFP57/KAP1 complex and that this is necessary for the proper maintenance of methylation imprints in mESCs
2017-12-07 | GSE90985 | GEO
Project description:ZFP57 is necessary for maintaining repressive epigenetic modifications at Imprinting control regions (ICRs). In mouse embryonic stem cells (ESCs), ZFP57 binds ICRs (ICRBS) and many other loci (non-ICRBS). To address the role of ZFP57 on all its target sites, we performed high-throughput and multi-locus analyses of inbred and hybrid mouse ESC lines carrying different gene knockouts. By using an allele-specific RNA-seq approach, we demonstrate that ZFP57 loss results in derepression of the imprinted allele of multiple genes in the imprinted clusters. We also find marked epigenetic differences between ICRBS and non-ICRBS suggesting that different cis-acting regulatory functions are repressed by ZFP57 at these two classes of target loci. Overall, these data demonstrate that ZFP57 is pivotal to maintain the allele-specific epigenetic modifications of ICRs that in turn are necessary for maintaining the imprinted expression over long distances. At non-ICRBS, ZFP57 inactivation results in acquisition of epigenetic features that are characteristic of poised enhancers, suggesting that another function of ZFP57 in early embryogenesis is to repress cis-acting regulatory elements whose activity is not yet required.
2016-06-04 | GSE77438 | GEO
Project description:ZFP57 is necessary for maintaining repressive epigenetic modifications at Imprinting control regions (ICRs). In mouse embryonic stem cells (ESCs), ZFP57 binds ICRs (ICRBS) and many other loci (non-ICRBS). To address the role of ZFP57 on all its target sites, we performed high-throughput and multi-locus analyses of inbred and hybrid mouse ESC lines carrying different gene knockouts. By using an allele-specific RNA-seq approach, we demonstrate that ZFP57 loss results in derepression of the imprinted allele of multiple genes in the imprinted clusters. We also find marked epigenetic differences between ICRBS and non-ICRBS suggesting that different cis-acting regulatory functions are repressed by ZFP57 at these two classes of target loci. Overall, these data demonstrate that ZFP57 is pivotal to maintain the allele-specific epigenetic modifications of ICRs that in turn are necessary for maintaining the imprinted expression over long distances. At non-ICRBS, ZFP57 inactivation results in acquisition of epigenetic features that are characteristic of poised enhancers, suggesting that another function of ZFP57 in early embryogenesis is to repress cis-acting regulatory elements whose activity is not yet required.
2016-06-04 | GSE77444 | GEO
Project description:ZFP57 is necessary for maintaining repressive epigenetic modifications at Imprinting control regions (ICRs). In mouse embryonic stem cells (ESCs), ZFP57 binds ICRs (ICRBS) and many other loci (non-ICRBS). To address the role of ZFP57 on all its target sites, we performed high-throughput and multi-locus analyses of inbred and hybrid mouse ESC lines carrying different gene knockouts. By using an allele-specific RNA-seq approach, we demonstrate that ZFP57 loss results in derepression of the imprinted allele of multiple genes in the imprinted clusters. We also find marked epigenetic differences between ICRBS and non-ICRBS suggesting that different cis-acting regulatory functions are repressed by ZFP57 at these two classes of target loci. Overall, these data demonstrate that ZFP57 is pivotal to maintain the allele-specific epigenetic modifications of ICRs that in turn are necessary for maintaining the imprinted expression over long distances. At non-ICRBS, ZFP57 inactivation results in acquisition of epigenetic features that are characteristic of poised enhancers, suggesting that another function of ZFP57 in early embryogenesis is to repress cis-acting regulatory elements whose activity is not yet required.
2016-06-04 | GSE77441 | GEO