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ZFP281 coordinates DNMT3 and TET1 in pluripotent state transitions [STEM-seq]

ABSTRACT: The progression and transition between the naïve, formative, and primed pluripotent states are accompanied by a sharp activation of the de novo DNA methyltransferases and the reorganization of transcriptional and epigenetic landscapes. Here we identified Zinc Finger Protein 281 (ZFP281) as an essential factor in the formative-to-primed pluripotent state transition. Using a knockout mouse model and a knockin degron cell system, we revealed that transcription of Dnmt3a/3b depends on the activity of ZFP281 in embryonic stem cells, epiblast-like cells, and epiblast stem cells. Mechanically, chromatin-bound ZFP281 and DNA hydroxylase TET1 are decreased in the formative state but recovered in the primed state to compete with DNMT3A/3B for establishing the DNA methylation and gene expression programs of primed pluripotency. In addition, chromatin occupancy of ZFP281 and TET1 depend on the R-loop structures formed at the ZFP281 target gene promoters devoid of DNA methylation. Our study demonstrates a comprehensive role of ZFP281 in modulating DNA methylation and demethylation for the establishment and maintenance of primed pluripotency.

ORGANISM(S): Mus musculus

PROVIDER: GSE227093 | GEO | 2023/12/14

REPOSITORIES: GEO

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ZFP281 coordinates DNMT3 and TET1 in pluripotent state transitions [RNA-seq]

Project description:The progression and transition between the naïve, formative, and primed pluripotent states are accompanied by a sharp activation of the de novo DNA methyltransferases and the reorganization of transcriptional and epigenetic landscapes. Here we identified Zinc Finger Protein 281 (ZFP281) as an essential factor in the formative-to-primed pluripotent state transition. Using a knockout mouse model and a knockin degron cell system, we revealed that transcription of Dnmt3a/3b depends on the activity of ZFP281 in embryonic stem cells, epiblast-like cells, and epiblast stem cells. Mechanically, chromatin-bound ZFP281 and DNA hydroxylase TET1 are decreased in the formative state but recovered in the primed state to compete with DNMT3A/3B for establishing the DNA methylation and gene expression programs of primed pluripotency. In addition, chromatin occupancy of ZFP281 and TET1 depend on the R-loop structures formed at the ZFP281 target gene promoters devoid of DNA methylation. Our study demonstrates a comprehensive role of ZFP281 in modulating DNA methylation and demethylation for the establishment and maintenance of primed pluripotency.

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Project description: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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