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| Status |
Public on Jun 03, 2016 |
| Title |
De novo DNA methyltransferases DNMT3A and DNMT3B are essential of global DNA methylation maintenance [RNA-Seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
DNA methylation is the net result of deposition by DNA methyltransferases (DNMT1, 3A and 3B) and removal by the Ten-Eleven Translocation 1-3 (TET1-3) family of proteins and/or passive loss by replication. The relative contribution of the individual enzymes and pathways is only partially understood. Here we comprehensively analyzed and mathematically simulated the dynamics of DNA de-methylation during the reprogramming of the hypermethylated serum-cultured mouse embryonic stem cells (ESCs) to the hypomethylated 2i-cultured ground state of mESC. We show that DNA demethylation readily occurs in TET[1-/-, 2-/-] ESCs with similar kinetics as their WT littermates. Vitamin C activation of TET causes accelerated and more profound DNA demethylation without markedly affecting reprogramming kinetics. We developed a mathematical model that highly accurately predicts the global level of 5methyl- and 5hydroxymethylcytosine during the transition. Modeling and experimental validation show that the concentration of DNMT3A and DNMT3B determines the steady state level of global DNA methylation and absence of DNMT3A/B even in continued presence of DNMT1 results in gradual loss of 5mC. Taken together, DNMT1 alone is insufficient to maintain DNA methylation but requires the action of DNMT3A/3B that act as a “dimmer switches”.
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| Overall design |
RNA-seq time series was performed during the early time phase of serum to 2i transition in the presence and absence of vitamin C (4h, 16h,24h, 32h), 1 replicate
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| Contributor(s) |
Habibi E, Liu NQ, Salehzadeh-Yazdi A, Yu M, Xie Z, Kroeze LI, Jansen JH, Xie H, He C, Stunnenberg HG |
| Citation(s) |
27237052 |
| |
| Submission date |
Jul 10, 2015 |
| Last update date |
May 15, 2019 |
| Contact name |
Hendrik G Stunnenberg |
| E-mail(s) |
H.Stunnenberg@ncmls.ru.nl
|
| Phone |
+31 (0)24 3610524
|
| Organization name |
Radboud University
|
| Department |
Molecular Biology
|
| Street address |
Geert Grooteplein 28
|
| City |
Nijmegen |
| ZIP/Postal code |
6525 GA |
| Country |
Netherlands |
| |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE70724 |
Impairment of DNA methylation maintenance is the main cause of global demethylation in naïve ES cells |
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| Relations |
| BioProject |
PRJNA289454 |
| SRA |
SRP060644 |
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