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E2F6 initiates stable epigenetic silencing of germline genes during embryonic development

ABSTRACT: In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes, however the molecular mechanisms of this specificity remain unclear. Here we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in vivo, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long term epigenetic silencing during mammalian development.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Embryonic Stem Cell

SUBMITTER: Johana Chicher

LAB HEAD: Michael Weber

PROVIDER: PXD023974 | Pride | 2021-04-22

REPOSITORIES: Pride

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Role of E2F6 in gene expression and DNA methylation during mouse development

Project description:In the mouse, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes in somatic cells, however the molecular mechanisms of this specificity remain unclear. Here we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in vivo, a function that critically depends on the E2F6 marked box domain. Furthermore, inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Finally, we show that E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long term epigenetic silencing during mammalian development.

2021-04-26 | GSE149025 | GEO

Systematic identification of factors involved in the silencing of germline genes in mouse embryonic stem cells

Project description:In mammals, many germline genes are repressed by epigenetic mechanisms to prevent their illegitimate expression in embryonic and somatic cells. To advance our understanding of the complete mechanisms restricting the expression of germline genes in mammals, we analyzed the chromatin signature of germline genes and performed a genome-wide CRISPR-Cas9 knock-out screen for genes involved in germline gene repression using a reporter system in which GFP is under the control of the epigenetically repressed Dazl germline promoter in mouse embryonic stem cells (ESCs). We showed that the repression of germline genes mainly depends on the polycomb complex PRC1.6 and DNA methylation, which function additively in mouse ESCs. Furthermore, we identified and validated several novel genes involved in the repression of germline genes, and characterized three of them: Usp7, Shfm1 (also known as Sem1) and Erh. Inactivation of Usp7, Shfm1 or Erh led to the upregulation of germline genes, as well as retrotransposons for Shfm1, in mouse ESCs. Functionally, Usp7 acts at two levels: firstly it associates with PRC1.6 components and represses germline genes independently of DNA methylation, and secondly it facilitates DNA methylation deposition at germline genes for long term repression. In summary, our study provides a global view of the epigenetic mechanisms and novel factors required for silencing germline genes in embryonic cells.

2023-02-03 | PXD030666 | Pride

KDM2B binds CpG islands and modulates recruitment of Ring1b

Project description:CpG island elements are associated with most mammalian gene promoters, yet how they contribute to gene regulation remains poorly understood. Recently it has become clear that a subset of CpG islands in embryonic stem cells can act as polycomb response elements and are recognized by the polycomb silencing systems to regulate the expression of genes involved in pluripotency and early developmental transcription programs. How CpG islands function mechanistically as nucleation sites for polycomb repressive complexes remains unknown. Here we discover that the KDM2B protein, by virtue of its ZF-CxxC DNA binding domain, specifically recognizes non-methylated DNA in CpG islands elements genome-wide. Through a physical interaction with the polycomb repressive complex 1 (PRC1), KDM2B targets PRC1 to CpG islands where it contributes to H2AK119ub1 and gene repression at a subset of polycomb targets. Unexpectedly, we also find that CpG islands are occupied by low levels of PRC1 throughout the genome, suggesting that the KDM2B-PRC1 complex may sample CpG island associated genes for susceptibility to polycomb mediated silencing. These observations demonstrate an unexpected and direct link between recognition of CpG islands by KDM2B and targeting of the polycomb repressive system. This provides the basis for a new model describing the functionality of CpG islands as mammalian PREs.

2012-12-26 | GSE40860 | GEO

A Stem Cell-Like Chromatin Pattern May Predispose Tumor Suppressor Genes to DNA Hypermethylation

Project description:Many cancers may originate in stem or early progenitor cells 1-4 which depend on epigenetic modulation of gene expression for normal function (ref). We have studied whether epigenetic states in cancers, and particularly abnormal gene silencing associated with promoter DNA hypermethylation in CpG rich regions (refs), may represent links between cancer and stem cell epigenetic patterns. We studied embryonal carcinomas (EC) which are malignancies of embryonic stem (ES) cells, but retain high potential for multi-lineage differentiation 5-8. Surprisingly, genes DNA hypermethylated and silenced in adult cancers are unmethylated in ES and EC cells. Remarkably, the promoter chromatin of the genes in EC cells is virtually identical to the same genes in adult cancers when the latter are induced to de-methylate. This chromatin, as recently reported for CpG island promoters of low expression, developmentally related, genes in ES cells (refs), is “bivalent” and contains both active and repressive histone modifications. The latter includes trimethyl lysine 27 of histone H3 (H3K27me3), which may recruit DNA methylation (refs), and the promoter regions are enriched for polycomb group (PcG) proteins which place this H3K27me3 mark. Thus, many genes which undergo abnormal DNA methylation and permanent silencing in adult cancers may be programmed to do so by a pre-existent stem cell-like chromatin pattern inherent to the cells in which they arise. Keywords: Stem cell epigenetics expression microarray

2007-10-26 | GSE4809 | GEO

KDM2B binds CpG islands and modulates recruitment of Ring1b

2012-12-26 | E-GEOD-40860 | biostudies-arrayexpress

The activity of the Caenorhabditis elegans Aquarius helicase EMB-4 enables the nuclear RNAi machinery to engage nascent RNA

Project description:Germline small RNA pathways initiate silencing of repetitive elements in animals and an interplay of nuclear small RNAs and chromatin modifications maintain this silencing, protecting the germline from spreading of transposable elements. In C. elegans germline, nuclear argonaute protein HRDE-1 initiates the transcriptional silencing pathway that is crucial for long term and heritable silencing of genes and repetitive regions. Here, we show that HRDE-1 interacts with components of the splicing machinery and the exon-junction complex. One such factor is the conserved RNA helicase EMB-4/AQR that binds introns and recruits the exon-junction proteins to newly spliced RNA. Our data shows that EMB-4/AQR is required for the transcriptional silencing pathway initiated by HRDE-1 and it functions by removing the intronic barriers to silencing thorugh its helicase function.

2017-06-30 | PXD004416 | Pride

Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer

Project description:RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggest that the epitranscriptome and its associated enzymes are altered in human tumors. In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in tranformed cell lines, identified the NOL1/NOP2/Sun domain family member 7 (NSUN7) as undergoing promoter CpG island hypermethylation-associated transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to found the RNA targets of this poorly characterized putative methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript instability. Most important, proteomics analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in those liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival and an immune-like signature, providing a potential attractive therapeutic niche for the current use of immune checkpoint inhibitors in hepatocellular carcinoma.

2023-05-10 | PXD038418 | Pride

Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer

2023-05-10 | PXD038422 | Pride

CpG islands recruit a histone H3 lysine 36 demethylase [Agilent data]

Project description:Transcription factors that bind small DNA motifs embedded in promoters play a central role in controlling gene expression. However, in addition to these elements, up to 70% of genes in higher eukaryotes also have high levels of non-methylated cytosine/guanine base pairs (CpGs) surrounding promoters and gene regulatory units. These features, called CpG islands, were identified over twenty years ago but there remains little mechanistic evidence to suggest how these enigmatic elements contribute to promoter function, with the exception that they are refractory to epigenetic silencing by DNA methylation. Here we show that CpG islands directly recruit the H3K36 specific lysine demethylase enzyme KDM2A. Genome wide analyses by ChIP-seq demonstrated a striking global association of KDM2A with CpG islands. Nucleation of KDM2A at these elements resulted in removal of H3K36 methylation creating CpG island chromatin that is uniquely depleted of this modification. KDM2A utilizes a zinc finger CxxC (ZF-CxxC) domain that specifically recognizes non-methylated CpG DNA and binding is blocked when the CpG DNA is methylated, thus constraining KDM2A to nonmethylated CpG islands. These data expose a remarkably straightforward mechanism through which KDM2A delineates a unique architecture that differentiates CpG island chromatin from bulk chromatin.

2010-04-27 | GSE21201 | GEO

Methylation profiling of leukemia cell lines

Project description:Methylation of CpG islands is associated with transcriptional repression and, in cancer, leads to the abnormal silencing of tumor-suppressor genes. We developed a novel and robust technique that allows the unbiased, genome wide detection of CpG-methylation in limited DNA samples, without applying methylation-sensitive restriction endonucleases or bisulfite-treatment. The approach is based on a recombinant, methyl-CpG binding protein that efficiently binds CpG-methylated DNA depending on its degree of CpG methylation. Its application in methyl-CpG immunoprecipitation (MCIp) facilitates the monitoring of CpG-island methylation on a genome wide level (in combination with CpG-island microarrays). The power of this novel approach was demonstrated by the profiling of three myeloid cell lines leading to the identification of more than a hundred aberrantly methylated CpG islands and many novel, putative tumor-suppressor genes. Keywords: MCIp on Chip

2006-05-10 | GSE4009 | GEO

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