A Primary Role of TET Proteins in Establishment and Maintenance of De Novo Bivalency at CpG Islands of Developmental Genes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA294136 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2191880.fastq.gz | Fastqsanger.gz | |||
| SRR2191890.fastq.gz | Fastqsanger.gz | |||
| SRR2191900.fastq.gz | Fastqsanger.gz | |||
| SRR2191881.fastq.gz | Fastqsanger.gz | |||
| SRR2191891.fastq.gz | Fastqsanger.gz |
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Project description:TET protein-catalyzed 5mC oxidation not only creates novel DNA modifications such as 5hmC, but also initiates active or passive DNA demethylation. However, the TETsâ function in crosstalk with specific histone modifications is largely elusive. Here, we show that TET2-mediated DNA demethylation plays a primary role in the de novo establishment and maintenance of H3K4me3/H3K27me3 bivalent domain underlying the methylated DNA CpG islands (CGIs). Overexpression of wild type (WT) but not catalytic inactive mutant (Mut) TET2 in TET-low-expressing cells results in increase of 5hmC level and accompanying DNA demethylation at a subset of CGIs. Importantly, this is sufficient to create de novo bivalent domains at these loci. Genome-wide analysis reveals that these de novo synthesized bivalent domains are largely associated with a subset of key developmental gene promoters, which are often located within CpG islands that are previously hyper-methylated and silenced. On the other hand, depletion of Tet1 and Tet2 in mouse ES cells results in an apparent loss of H3K27me3 at bivalent domains, which are located within CGIs and associated with a particular set of key developmental gene promoters. Collectively, these data suggest that TET proteins have a primary role in charge of regulating the crosstalk between two key epigenetic mechanisms, DNA methylation and histone methylation (H3K4me3 and H3K27me3), particularly at a subset of CpG islands associated with developmental genes. We examined H3K4me3,H3K27me3,5mC and 5hmC in 293T and mES cell types,using Illumina Hiseq2500.
2016-07-25 | E-GEOD-72481 | biostudies-arrayexpress
Project description:TET protein-catalyzed 5mC oxidation not only creates novel DNA modifications such as 5hmC, but also initiates active or passive DNA demethylation. However, the TETs’ function in crosstalk with specific histone modifications is largely elusive. Here, we show that TET2-mediated DNA demethylation plays a primary role in the de novo establishment and maintenance of H3K4me3/H3K27me3 bivalent domain underlying the methylated DNA CpG islands (CGIs). Overexpression of wild type (WT) but not catalytic inactive mutant (Mut) TET2 in TET-low-expressing cells results in increase of 5hmC level and accompanying DNA demethylation at a subset of CGIs. Importantly, this is sufficient to create de novo bivalent domains at these loci. Genome-wide analysis reveals that these de novo synthesized bivalent domains are largely associated with a subset of key developmental gene promoters, which are often located within CpG islands that are previously hyper-methylated and silenced. On the other hand, depletion of Tet1 and Tet2 in mouse ES cells results in an apparent loss of H3K27me3 at bivalent domains, which are located within CGIs and associated with a particular set of key developmental gene promoters. Collectively, these data suggest that TET proteins have a primary role in charge of regulating the crosstalk between two key epigenetic mechanisms, DNA methylation and histone methylation (H3K4me3 and H3K27me3), particularly at a subset of CpG islands associated with developmental genes.
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Project description:Ten Eleven Translocation (TET) protein-catalyzed 5mC oxidation not only creates novel DNA modifications, such as 5hmC, but also initiates active or passive DNA demethylation. TETs' role in the crosstalk with specific histone modifications, however, is largely elusive. Here, we show that TET2-mediated DNA demethylation plays a primary role in the de novo establishment and maintenance of H3K4me3/H3K27me3 bivalent domains underlying methylated DNA CpG islands (CGIs). Overexpression of wild type (WT), but not catalytic inactive mutant (Mut), TET2 in low-TET-expressing cells results in an increase in the level of 5hmC with accompanying DNA demethylation at a subset of CGIs. Most importantly, this alteration is sufficient in making de novo bivalent domains at these loci. Genome-wide analysis reveals that these de novo synthesized bivalent domains are largely associated with a subset of essential developmental gene promoters, which are located within CGIs and are previously silenced due to DNA methylation. On the other hand, deletion of Tet1 and Tet2 in mouse embryonic stem (ES) cells results in an apparent loss of H3K27me3 at bivalent domains, which are associated with a particular set of key developmental gene promoters. Collectively, this study demonstrates the critical role of TET proteins in regulating the crosstalk between two key epigenetic mechanisms, DNA methylation and histone methylation (H3K4me3 and H3K27me3), particularly at CGIs associated with developmental genes.
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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.
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Project description:DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2 and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. Affinity purification of PROSER1 resulted in the identification of OGT and TET1-3. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. Additionally, PROSER1, UTX, OGT, and TET1/2 colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, and TET1/2 at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional downregulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands.
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Project description:DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2 and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. Affinity purification of PROSER1 resulted in the identification of OGT and TET1-3. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. Additionally, PROSER1, UTX, OGT, and TET1/2 colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, and TET1/2 at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional downregulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands.
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Project description:DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2 and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. Affinity purification of PROSER1 resulted in the identification of OGT and TET1-3. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. Additionally, PROSER1, UTX, OGT, and TET1/2 colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, and TET1/2 at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional downregulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands.
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Project description:DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2 and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. Affinity purification of PROSER1 resulted in the identification of OGT and TET1-3. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. Additionally, PROSER1, UTX, OGT, and TET1/2 colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, and TET1/2 at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional downregulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands.
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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. ChIP-Seq to compare KDM2A vs. KDM2B genome-wide binding profiles and to understand the contribution of KDM2B to RING1B nucleation. Binding of Kdm2a and Kdm2b to the genome was examined in wildtype mESC, and Kdm2b and Ring1b in mESC where Kdm2b has been stably knocked down by shRNA.
2012-12-26 | E-GEOD-40860 | biostudies-arrayexpress