Impaired DNA demethylation of C/EBP sites causes premature aging

Schäfer, Andrea; Mekker, Bernadette; Mallick, Medhavi; Vastolo, Viviana; Karaulanov, Emil; Sebastian, Dominik; Lippen, Carina von der; Epe, Bernd; Downes, Damien J.; Scholz, Carola; Niehrs, Christof

doi:10.1101/gad.311969.118

Cited by 32 publications

(25 citation statements)

References 134 publications

(206 reference statements)

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“…Enhancers in ESCs tend to be hypomethylated (Stadler et al 2011;Kieffer-Kwon et al 2013;Ziller et al 2013), and thus GADD45 plays a significant role in this phenomenon. Enhancers are also the main target of GADD45α-mediated DNA demethylation in mouse embryonic fibroblasts (MEFs) (Schäfer et al 2018).…”

Section: Tet/tdg Processed Sites Are Main Targets Of Gadd45mediated Dmentioning

confidence: 99%

“…GADD45α is an adapter protein that tethers TET/TDG to sites of DNA demethylation, which functions in locus-specific DNA demethylation (Barreto et al 2007;Li et al 2010;Cortellino et al 2011;Zhang et al 2011a;Arab et al 2014;Sabag et al 2014). GADD45α recruits TET/TDG to specific sites in the genome via additional cofactors (Schäfer et al 2013;Arab et al 2014Arab et al , 2019Schäfer et al 2018).…”

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confidence: 99%

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GADD45 promotes locus-specific DNA demethylation and 2C cycling in embryonic stem cells

et al. 2019

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Mouse embryonic stem cell (ESC) cultures contain a rare cell population of "2C-like" cells resembling two-cell embryos, the key stage of zygotic genome activation (ZGA). Little is known about positive regulators of the 2C-like state and two-cell stage embryos. Here we show that GADD45 (growth arrest and DNA damage 45) proteins, regulators of TET (TET methylcytosine dioxygenase)-mediated DNA demethylation, promote both states. Methylome analysis of Gadd45a,b,g triple-knockout (TKO) ESCs reveal locus-specific DNA hypermethylation of ∼7000 sites, which are enriched for enhancers and loci undergoing TET-TDG (thymine DNA glycosylase)-mediated demethylation. Gene expression is misregulated in TKOs, notably upon differentiation, and displays signatures of DNMT (DNA methyltransferase) and TET targets. TKOs manifest impaired transition into the 2C-like state and exhibit DNA hypermethylation and down-regulation of 2C-like state-specific genes. Gadd45a,b double-mutant mouse embryos display embryonic sublethality, deregulated ZGA gene expression, and developmental arrest. Our study reveals an unexpected role of GADD45 proteins in embryonic two-cell stage regulation.

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Section: Tet/tdg Processed Sites Are Main Targets Of Gadd45mediated Dmentioning

confidence: 99%

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confidence: 99%

GADD45 promotes locus-specific DNA demethylation and 2C cycling in embryonic stem cells

et al. 2019

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“…However, whether homo/heterodimers of BmC/EBPg activate BmCBP expression requires further investigation. C/EBPs are also well-known CCAAT/EBPs and are widely reported to be involved in many cellular processes, such as cell growth and aging (Buck et al, 1999;Schafer et al, 2018), differentiation Radomska et al, 1998;AlSudais et al, 2018;Jeong et al, 2019), injury and inflammation response (Burgess-Beusse and Darlington, 1998;Poli, 1998;Jo et al, 2018), and cellular phenotypes (Lekstrom-Himes and Xanthopoulos, 1998;Salaroglio et al, 2018). In mammals, C/EBPs play pivotal roles in immunoresponse (Dai et al, 2017;Larabee et al, 2018), inflammatory response, liver regeneration, metabolism and numerous diseases (Ramji and Foka, 2002;Pulikkan et al, 2017;Wattanavanitchakorn et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

20‐Hydroxyecdysone receptor‐activated Bombyx mori CCAAT/enhancer‐binding protein gamma regulates the expression of BmCBP and subsequent histone H3 lysine 27 acetylation in Bo. mori

Lyu

Chen

et al. 2020

Insect Molecular Biology

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Cyclic adenosine monophosphate (cAMP) response element binding protein (CREB)‐binding protein (CBP or CREBBP) plays important roles in regulating gene transcription and animal development. However, the process by which CBP is up‐regulated to impact insect development is unknown. In this study, the regulatory mechanism of Bombyx mori CBP (BmCBP) expression induced by 20‐hydroxyecdysone (20E) was investigated. In the Bo. mori cell line, DZNU‐Bm‐12, 20E enhanced BmCBP transcription and histone H3K27 acetylation. BmCBP RNA interference (RNAi) resulted in decreased histone H3K27 acetylation. Additionally, the luciferase activity analysis revealed that the transcription factor, Bo. mori CCAAT/enhancer‐binding protein gamma (BmC/EBPg), activated BmCBP transcription, which was suppressed by BmC/EBPg RNAi and promoted by BmC/EBPg overexpression. Electrophoretic mobility shift assay and chromatin immunoprecipitation results demonstrated that BmC/EBPg could bind to the C/EBP cis‐regulatory elements in two positions of the BmCBP promoter. Moreover, BmC/EBPg transcription was enhanced by the 20E receptor (BmEcR), which bound to the BmC/EBPg promoter. BmEcR RNAi significantly inhibited the transcriptional levels of BmC/EBPg and BmCBP in the presence of 20E. Furthermore, the BmEcR‐BmC/EBPg pathway regulated the acetylation levels of histone H3K27. Altogether, these results indicate that BmEcR enhances the expression of BmC/EBPg, which binds to the BmCBP promoter, activates BmCBP expression and leads to histone H3K27 acetylation.

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“…Current data on the C/EBP proteins, including CEBPA and CEBPB, suggest that they are tightly involved in establishing the methylation status of the regulatory regions (Schäfer et al, 2018), which is linked to high-level processes such as energy metabolism and longevity (Niehrs and Calkhoven, 2020). Targeted somatic mutagenesis of C/EBP sites in adult stem cells might be yet another contribution to aging or malignant cell transformation.…”

Section: Model Of Selective Fixation Of [C>t]g Mutations Through Enhamentioning

confidence: 99%

Enhanced C/EBPs binding to C>T mismatches facilitates fixation of CpG mutations

Ershova

Eliseeva

Nikonov

et al. 2020

Preprint

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Knowledge of mechanisms responsible for mutagenesis of adult stem cells is crucial to track genomic alterations that may affect cell renovation and provoke malignant cell transformation. Mutations in regulatory regions are widely studied nowadays, though mostly in cancer. In this study, we decomposed the mutation signature of adult stem cells, mapped the corresponding mutations into transcription factor binding regions, and assessed mutation frequency in sequence motif occurrences. We found binding sites of C/EBP transcription factors strongly enriched with [C>T]G mutations within the core CG dinucleotide related to deamination of the methylated cytosine. This effect was also exhibited in related cancer samples. Structural modeling predicted enhanced CEBPB binding to the consensus sequence with the [C>T]G mismatch, which was then confirmed in the direct experiment. We propose that it is the enhanced binding of C/EBPs that shields C>T transitions from DNA repair and leads to selective accumulation of the [C>T]G mutations within binding sites.

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Impaired DNA demethylation of C/EBP sites causes premature aging

Cited by 32 publications

References 134 publications

GADD45 promotes locus-specific DNA demethylation and 2C cycling in embryonic stem cells

GADD45 promotes locus-specific DNA demethylation and 2C cycling in embryonic stem cells

20‐Hydroxyecdysone receptor‐activated Bombyx mori CCAAT/enhancer‐binding protein gamma regulates the expression of BmCBP and subsequent histone H3 lysine 27 acetylation in Bo. mori

Enhanced C/EBPs binding to C>T mismatches facilitates fixation of CpG mutations

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