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DNA sequence determines epigenetic bistability at imprinting control regions [BS-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE176460 | GEO | 2022/07/20

REPOSITORIES: GEO

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DNA sequence determines epigenetic bistability at imprinting control regions [ChIP-Seq]

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

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

2022-07-20 | GSE203404 | GEO

DNA sequence and chromatin modifiers cooperate to confer epigenetic bistability at imprinting control regions

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

Wnt/β-catenin signaling pathway safeguards epigenetic stability and homeostasis of mouse embryonic stem cells.

Project description:Wnt/β-catenin signaling regulates both mouse embryonic stem cell (mESC) self-renewal and differentiation. Here we show that the activity of the Wnt/β-catenin signaling pathway safeguards normal DNA methylation of mESCs. Indeed, loss of Wnt activity correlated with loss of DNA methylation, especially at the imprinting control regions (ICRs) in prolonged in vitro mESC cultures. To address the role of Wnt signaling on ICR methylation we performed Reduced Representation Bisulfite Sequencing (RRBS) on both “Young” and “Old” mESCs, being at early and late passages, respectively. We found that several ICRs (both maternal and paternal) showed loss of methylation in “Old” cells that correlates with lower Wnt downstream target expression and lower β-catenin protein level, when compared to “Young” mESCs. In parallel, we analyzed the ICR methylation level also in two Wnt mutant clones after prolonged in vitro culture (O-S33Y #1 and #2). The mutant clones maintained high Wnt activity with passages, similar to “Young” mESCs and ICR methylation level at around 50%, further supporting the beneficial role of Wnt/β-catenin pathway on mESC epigenetic stability and homeostasis.

2019-02-07 | GSE109417 | GEO

TRIM28-Regulated Transposon Repression Is Required for Human Germline Competency and Not Primed or Naive Human Pluripotency

Project description:Transition from primed to naive pluripotency is associated with dynamic changes in transposable element (TE) expression and demethylation of imprinting control regions (ICRs). In mouse, ICR methylation and TE expression are each regulated by TRIM28; however, the role of TRIM28 in humans is less clear. Here, we show that a null mutation in TRIM28 causes significant alterations in TE expression in both the naive and primed states of human pluripotency, and phenotypically this has limited effects on self-renewal, instead causing a loss of germline competency. Furthermore, we discovered that TRIM28 regulates paternal ICR methylation and chromatin accessibility in the primed state, with no effects on maternal ICRs. Taken together, our study shows that abnormal TE expression is tolerated by self-renewing human pluripotent cells, whereas germline competency is not.

2018-01-04 | GSE99215 | GEO

Role of N-α-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting

Project description:Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR), of which the underlying mechanism remains largely unclear. Mammalian N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins. Mutation of human Naa10p is linked to severe developmental delays. Here we report that Naa10-null mice display partial embryonic lethality, growth retardation, brain disorder and maternaleffect lethality, phenotypes commonly observed in defective genomic imprinting. Genome-wide analyses further revealed global DNA hypomethylation and enriched dysregulation of imprinted genes in Naa10p-knockout embryos and ES cells. Mechanistically, Naa10p facilitates the binding of DNA methyltransferase 1 (Dnmt1) to DNA substrates and recruits Dnmt1 to ICRs of the imprinted allele during S phase. Moreover, the clinical lethal Ogden syndrome-associated mutation of Naa10p disrupts its binding to H19-ICR and Dnmt1 recruitment. Our study thus links Naa10p mutationassociated human disease to defective DNA methylation and genomic imprinting.

2017-10-05 | GSE102224 | GEO

Allele-specific regulation of gene expression through enhancer function and transcriptional elongation control at imprinted loci

Project description:Genomic imprinting is a critical developmental process characteristic of parent-of-origin- specific gene expression. Here, we have identified the AFF family protein, Aff3, as a factor that functionally interacts with imprinted loci. Indeed, our genome-wide studies demonstrate that Aff3 specifically binds both imprinting control regions (ICRs) and enhancers within imprinted loci in an allele-specific manner. We have identified the molecular regulators involved in the recruitment of Aff3 to ICRs to impede transcription through the ICR, and provide a mechanism requiring Aff3 within the Super Elongation Complex-like 3 (SEC-L3) in the expression of an imprinted polycistronic transcript spanning the Dlk1-Dio3 locus. Our study also shows that DNA methylation at the ICR reinforces silencing of its related enhancers by controlling the binding and activity of Aff3 in an allele-specific manner. This study provides molecular details about the regulation of dosage-critical imprinted gene expression through Aff3’s function in transcriptional elongation control.

2016-01-01 | GSE64489 | GEO

Allele-specific regulation of gene expression through enhancer function and transcriptional elongation control at imprinted loci

2016-07-03 | E-GEOD-64489 | biostudies-arrayexpress

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.

2019-06-18 | GSE111173 | GEO

IMPLICON: a high-resolution method to uncover DNA methylation at imprinted regions

Project description:Genomic imprinting is an epigenetic phenomenon leading to parental allele specific expression. Dosage of imprinted genes is crucial for normal development and its dysregulation accounts for a number of human disorders. Imprinted expression is dictated by differences in DNA methylation between parental alleles at specific regulatory elements known as imprinting control regions (ICRs). Although a number of approaches can be used for methylation inspection at ICRs, we lack an easy and cost-effective method to simultaneously measure DNA methylation at multiple imprinted regions. Here, we present IMPLICON, a new high-throughput method measuring DNA methylation levels at imprinted regions with base-pair resolution and over 1000-fold genomic coverage. We initially designed this method to look at ICRs in adult tissues of inbred mice. Then, we validated in hybrid mice from reciprocal crosses for which we could discriminate methylation profiles in the two parental alleles. Lastly, we developed a human version of IMPLICON and detected imprinting errors in naïve human embryonic and induced pluripotent stem cells. We also provide rules and guidelines in which this method can be adapted to investigate the DNA methylation landscape of any set of genomic regions. In summary, IMPLICON is a rapid, cost-effective and scalable method, which could become the gold standard in both imprinting research and diagnostics.

2020-06-22 | GSE146129 | GEO

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