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TET1 (HUES8 WT hESCs) and DNMT3B (HUES8 WT and HUES8 TET TKO hESCs) ChIP-Seq

ABSTRACT: The TET enzymes oxidize 5-methylcytosine to 5-hydroxymethylcytosine, which can lead to DNA demethylation. However, direct connections between TET-mediated DNA demethylation and transcriptional output are difficult to establish due to challenges of distinguishing global versus locus-specific effects. Here we show that TET1/2/3 triple knockout (TKO) human embryonic stem cells (hESCs) exhibit preferential hypermethylation at bivalent promoters without corresponding gene expression changes in undifferentiated hESCs. In the absence of the TET proteins, abnormal accumulation of DNMT3B at bivalent promoters results in hypermethylation and impaired gene activation upon differentiation. Broadly, the competitive balance between the TET proteins and de novo methyltransferases at bivalent promoters could facilitate rapid changes of their methylation state to either activate or silence transcription in a cell-lineage and gene dependent manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99346 | GEO | 2017/12/01

SECONDARY ACCESSION(S): PRJNA388168

REPOSITORIES: GEO

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RNA Sequencing of HUES8 WT and HUES8 TET1/2/3 TKO hESCs

Project description:The TET enzymes oxidize 5-methylcytosine to 5-hydroxymethylcytosine, which can lead to DNA demethylation. However, direct connections between TET-mediated DNA demethylation and transcriptional output are difficult to establish due to challenges of distinguishing global versus locus-specific effects. Here we show that TET1/2/3 triple knockout (TKO) human embryonic stem cells (hESCs) exhibit preferential hypermethylation at bivalent promoters without corresponding gene expression changes in undifferentiated hESCs. In the absence of the TET proteins, abnormal accumulation of DNMT3B at bivalent promoters results in hypermethylation and impaired gene activation upon differentiation. Broadly, the competitive balance between the TET proteins and de novo methyltransferases at bivalent promoters could facilitate rapid changes of their methylation state to either activate or silence transcription in a cell-lineage and gene dependent manner.

2017-12-01 | GSE89726 | GEO

Reduced Representation Bisulfite Sequencing of HUES8 WT and HUES8 TET1/2/3 TKO hESCs

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RNA Sequencing of WT and TET TKO cells at different developmental stages

Project description:Changes in DNA methylation are associated with normal cardiogenesis, while altered methylation patterns can occur in congenital heart disease. Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) and promote locus-specific DNA demethylation. Here we characterize stage-specific methylation dynamics and the function of TETs during directed differentiation of human embryonic stem cells (hESCs) to cardiomyocyte (CM) fate. No defect is observed using isogenic TET2, TET3 or TET2/3 double knockout lines, while TET1 knockout lines display a significant decrease in capacity to generate CTNT+ CMs. Moreover, hESCs in which all three TET genes are inactivated (TET TKO hESCs) fail entirely to generate CMs. TET-deficient cells display altered mesoderm patterning and defective cardiac progenitor specification. Genome-wide methylation analysis shows that TETs are required first to maintain hypomethylation of early regulatory genes, and subsequently for demethylation of cardiac structural genes. Mechanistically, TET knockout causes promoter hypermethylation of genes encoding WNT inhibitors, leading to hyperactivated WNT signaling and defects in cardiac mesoderm patterning. TET activity is also needed to maintain hypomethylated status and expression of NKX2-5 for subsequent cardiac progenitor specification. Finally, loss of TETs causes a set of cardiac structural genes to fail to be demethylated at the cardiac progenitor stage. Our data demonstrate key roles for TET proteins to control methylation dynamics at sequential steps during human cardiac development.

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5-hydroxymethylcytosine (5hmC) profiling of H1 WT hESCs

Project description:DNA methylation is essential to mammalian development, and aberrant regulation can lead to disease. The enzymes responsible for deposition and removal of DNA methylation have been identified, but how tightly regulated DNA methylation patterns are achieved globally remains a central question. To discover regulators of DNA methylation in human Embryonic Stem Cells (hESCs), we engineered a DNA methylation reporter line and performed a genome-wide CRISPR/Cas screen. Through our screen, we identified the functionally uncharacterized gene QSER1, which proved to be essential for protection from DNA hypermethylation at bivalent promoters and poised enhancers of developmental genes, especially those residing in DNA Methylation Valleys (DMVs). Further mechanistic enquiry revealed that QSER1 protein depends on TET1 for efficient recruitment to DNA, and QSER1 occupancy inhibits the binding of DNMT3B. Our discovery of QSER1 is a major advance in understanding TET-dependent protection from DNA hypermethylation and provides mechanistic insight into how epigenetic factors can cooperate to target locus-specific regulation.

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ERRBS of WT and TET TKO cells from stem cell (SC) to cardiomyocyte (CM)

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Homo sapiens strain:HUES8 hESCs

Project description:HUES8 TET1/2/3 TKO hESCs RNA Sequencing

| PRJNA352092 | ENA

RNA Sequencing of H1 WT hESCs, H1 QSER1 KO hESCs, H1 TET1 KO hESCs, H1 QSER1/TET1 DKO hESCs, WT Day10 EBs, QSER1 KO Day10 EBs, TET1 KO Day10 EBs, QSER1/TET1 DKO Day10 EBs, WT PP1, QSER1 KO PP1, TET1 KO PP1, and QSER1/TET1 DKO PP1.

Project description:RNA Sequencing of H1 WT hESCs, H1 QSER1 KO hESCs, H1 TET1 KO hESCs, H1 QSER1/TET1 DKO hESCs, WT Day10 embryoid bodies (EBs), QSER1 KO Day10 EBs, TET1 KO Day10 EBs, QSER1/TET1 DKO Day10 EBs, WT pancreatic progenitors (PP1), QSER1 KO PP1, TET1 KO PP1, and QSER1/TET1 DKO PP1. DNA methylation is essential to mammalian development, and dysregulation can cause serious pathological conditions. Key enzymes responsible for deposition and removal of DNA methylation are known, but how they cooperate to tightly regulate the methylation landscape remains a central question. Utilizing a knockin DNA methylation reporter, we performed a genome-wide CRISPR/Cas screen in human embryonic stem cells to discover DNA methylation regulators. The top screen hit was an uncharacterized gene QSER1, which proved to be a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those residing in DNA methylation valleys (or canyons). We further demonstrate cooperation of QSER1 and TET1 through genetic and biochemical interactions to inhibit DNMT3-mediated de novo methylation and safeguard developmental programs.

2021-03-19 | GSE169209 | GEO

A Primary Role of TET Proteins in Establishment and Maintenance of De Novo Bivalency at CpG Islands of Developmental Genes

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

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