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TDG orchestrates ATF4-dependent gene transcription during retinoic acid-induced cell lineage committment

ABSTRACT: Cell differentiation during development is associated to large-scale modifications in the methylome that require the engagement of an active DNA demethylation machinery including Ten-Eleven-Translocation enzymes for oxidation of 5-methylcytosine and the T:G mismatch DNA glycosylase (TDG) for removal of the oxidized bases. Despite this well-defined molecular function, the biological output of TDG activity remains elusive. Here we combined transcriptomic and epigenomic approaches in TDG knock-out embryonal carcinoma cells, an epiblast stem-like cell model, to decipher TDG function in pluripotent cells and their retinoic acid-induced differentiated progeny. We determined that TDG activity is balancing differentiation in favor of a neural fate at the expense of a cardiac mesoderm fate. This process is associated with a sustained activity of a large set of ATF4-dependent genes in relation with TDG engagement at the Atf4 gene promoter and in conjunction with a TDG-dependent regulation of the mammalian target of rapamycin complex 1. These observations highlight the central role of TDG in cell differentiation and support a model linking metabolic reprogramming to cell fate acquisition.

ORGANISM(S): Mus musculus

PROVIDER: GSE262587 | GEO | 2024/03/31

REPOSITORIES: GEO

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TDG orchestrates ATF4-dependent gene transcription during retinoic acid-induced cell lineage committment

Project description:Cell differentiation during development is associated to large-scale modifications in the methylome that require the engagement of an active DNA demethylation machinery including Ten-Eleven-Translocation enzymes for oxidation of 5-methylcytosine and the T:G mismatch DNA glycosylase (TDG) for removal of the oxidized bases. Despite this well-defined molecular function, the biological output of TDG activity remains elusive. Here we combined transcriptomic and epigenomic approaches in TDG knock-out embryonal carcinoma cells, an epiblast stem-like cell model, to decipher TDG function in pluripotent cells and their retinoic acid-induced differentiated progeny. We determined that TDG activity is balancing differentiation in favor of a neural fate at the expense of a cardiac mesoderm fate. This process is associated with a sustained activity of a large set of ATF4-dependent genes in relation with TDG engagement at the Atf4 gene promoter and in conjunction with a TDG-dependent regulation of the mammalian target of rapamycin complex 1. These observations highlight the central role of TDG in cell differentiation and support a model linking metabolic reprogramming to cell fate acquisition.

2024-03-19 | GSE261602 | GEO

Thymine DNA glycosylase (TDG) regulates cell cycle–driven p53 transcriptional control in pluripotent cells

Project description:Cell cycle progression is linked to transcriptome dynamics and variations in the response of pluripotent cells to differentiation cues, through mostly unknown determinants. Here, we characterized the cell cycle–associated transcriptome and proteome of mouse embryonic stem cells (mESCs) in naïve ground state. We found that the thymine DNA glycosylase (TDG) is a cell cycle–regulated co-factor of the tumour suppressor p53. Further, TDG and p53 co-bind ESC-specific cis-regulatory elements and thereby control transcription of p53-dependent genes during self-renewal. We determined that the dynamic expression of TDG is required to promote the cell cycle–associated transcriptional heterogeneity. Moreover, we demonstrated that transient depletion of TDG influences cell fate decisions during the early differentiation of mESCs. Our findings reveal an unanticipated role of TDG in promoting molecular heterogeneity during the cell cycle, and highlight the central role of protein dynamics for the temporal control of cell fate during development.

2023-07-31 | PXD029596 | Pride

Effects of Tdg deficiency on overall transcription in mouse embryonic fibroblasts and during cell differentiation

Project description:Because it excises thymine from GM-bM-^@M-"T mismatches, TDG was proposed to counter mutagenesis by 5-methylcytosine deamination. Yet, TDG was also observed to attack 5-methycytosine itself, making it a candidate DNA demethylase, and interactions with transcription factors implicated additional functions in gene regulation. Unlike other DNA glycosylases, TDG is essential for embryonic development. Fibroblasts from Tdg null embryos show massively impaired gene regulation, and this correlates with imbalanced histone modification and CpG methylation. TDG associates with the promoters of affected genes in MEFs and in embryonic stem cells, but epigenetic aberrations appear only in differentiated cells. TDG also contributes to the maintenance of active and bivalent chromatin during cell differentiation, using its DNA glycosylase activity to counter aberrant de novo methylation. Thus, TDG dependent DNA repair stabilizes epigenetic states during cell differentiation. Comparison of 3 Tdg+/- MEF replicates with 3 Tdg-/- MEF replicates. Comparison of Tdg+/- and Tdg-/- ES cells and respective in vitro differentiated neuronal progenitors. Each condition is represented by 3 replicas.

2011-01-31 | E-GEOD-20693 | biostudies-arrayexpress

Effects of Tdg deficiency on overall transcription in mouse embryonic fibroblasts and during cell differentiation

Project description:Because it excises thymine from G•T mismatches, TDG was proposed to counter mutagenesis by 5-methylcytosine deamination. Yet, TDG was also observed to attack 5-methycytosine itself, making it a candidate DNA demethylase, and interactions with transcription factors implicated additional functions in gene regulation. Unlike other DNA glycosylases, TDG is essential for embryonic development. Fibroblasts from Tdg null embryos show massively impaired gene regulation, and this correlates with imbalanced histone modification and CpG methylation. TDG associates with the promoters of affected genes in MEFs and in embryonic stem cells, but epigenetic aberrations appear only in differentiated cells. TDG also contributes to the maintenance of active and bivalent chromatin during cell differentiation, using its DNA glycosylase activity to counter aberrant de novo methylation. Thus, TDG dependent DNA repair stabilizes epigenetic states during cell differentiation.

2011-01-31 | GSE20693 | GEO

Gadd45a promotes DNA demethylation through TDG

Project description:Growth arrest and DNA-damage-inducible protein 45 (Gadd45) family members have been implicated in DNA demethylation in vertebrates. However, it remained unclear how they contribute to the demethylation process. Here, we demonstrate that Gadd45a promotes active DNA demethylation through thymine DNA glycosylase (TDG) which has recently been shown to excise 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) generated in Ten-eleven-translocation (Tet) -initiated oxidative demethylation. The connection of Gadd45a with oxidative demethylation is evidenced by the enhanced activation of a methylated reporter gene in HEK293T cells expressing Gadd45a in combination with catalytically active TDG and Tet. Gadd45a interacts with TDG physically and increases the removal of 5fC and 5caC from genomic and transfected plasmid DNA by TDG. Knockout of both Gadd45a and Gadd45b from mouse ES cells leads to hypermethylation of specific genomic loci most of which are also targets of TDG and show 5fC enrichment in TDG-deficient cells. These observations indicate that the demethylation effect of Gadd45a is mediated by TDG activity. This finding thus unites Gadd45a with the recently defined Tet-initiated demethylation pathway. The dataset includes RRBS anlysis of 2 WT ES cell samples and 2 Gadd45a/b DKO ES cell samples.

2015-05-07 | E-GEOD-62496 | biostudies-arrayexpress

Gadd45a promotes DNA demethylation through TDG

2015-05-07 | GSE62496 | GEO

Genome-wide analysis reveals TET- and TDG-mediated 5-methylcytosine oxidation dynamics

Project description:Ten-eleven translocation (Tet) family of DNA dioxygenases converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5- carboxylcytosine (5caC) through iterative oxidation reactions. While 5mC and 5hmC are relatively abundant, 5fC and 5caC are at very low levels in the mammalian genome. Thymine DNA glycosylase (TDG) and base excision repair (BER) pathways can actively remove 5fC/5caC to regenerate unmethylated cytosine, but it is unclear to what extent and at which part of the genome such active demethylation processes take place. Here, we have performed high-throughput sequencing analysis of 5mC/5hmC/5fC/5caC- enriched DNA using modification-specific antibodies and generated genome-wide distribution maps of these cytosine modifications in wild-type and Tdg-deficient mouse embryonic stem cells (ESCs). We observe that the steady state 5fC and 5caC are preferentially detected at repetitive sequences in wild-type mouse ESCs. Depletion of TDG causes marked accumulation of 5fC and 5caC at a large number of distal gene regulatory elements and transcriptionally repressed/poised gene promoters, suggesting that Tet/TDG-dependent dynamic cycling of 5mC oxidation states may be involved in regulating the function of these regions. Thus, comprehensive mapping of 5mC oxidation and BER pathway activity in the mammalian genome provides a promising approach for better understanding of biological roles of DNA methylation and demethylation dynamics in development and diseases. Refer to individual Series

2013-04-18 | E-GEOD-42250 | biostudies-arrayexpress

Genome-wide analysis reveals TET- and TDG-mediated 5-methylcytosine oxidation dynamics [Expression]

2013-04-18 | E-GEOD-46112 | biostudies-arrayexpress

Genome-wide analysis reveals TET- and TDG-mediated 5-methylcytosine oxidation dynamics [MeDIP-Seq]

2013-04-18 | E-GEOD-46111 | biostudies-arrayexpress

Roles of TET and TDG in DNA demethylation in proliferating and non-proliferating immune cells [RNA-seq]

Project description:TET enzymes mediate DNA demethylation by oxidizing 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Because these oxidized methylcytosines (oxi-mC) are not recognized by the maintenance methyltransferase DNMT1, DNA demethylation can occur through “passive”, replication-dependent dilution as cells divide. A distinct, replication-independent (“active”) mechanism of DNA demethylation involves excision of 5fC and 5caC by the DNA repair enzyme thymine DNA glycosylase (TDG), followed by base excision repair. Here we used inducible gene-disrupted mice to show that TET enzymes influence both replication-dependent primary T cell differentiation and replication-independent macrophage differentiation, whereas TDG has no effect. Mice with long-term (1 year) deletion of Tdg are healthy and show normal survival and hematopoiesis. In summary, TET enzymes regulate differentiation and DNA demethylation primarily through passive dilution of oxidized methylcytosines in replicating T cells, and active, replication-independent DNA demethylation mediated by TDG does not appear to be essential for immune cell activation or differentiation.

2021-05-13 | GSE163894 | GEO

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