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DNMT3L safeguards the epigenome and differentiation potential of human naive pluripotent stem cells and blastoids [sciMET]

ABSTRACT: Studies of the catalytically inactive DNA methyltransferase Dnmt3l have mainly been limited to mice where Dnmt3l was shown to be essential for fertility, de novo DNA methylation in early embryos and maintenance of DNA methylation patterns in mouse pluripotent stem cells. In humans, recent work revealed that DNMT3L is the most highly enriched chromatin factor in naive pluripotent stem cells (hPSCs) compared with primed hPSCs. Naive hPSCs and stem cell-based human embryo models provide a unique opportunity to functionally the role of DNMT3L in human naive pluripotent and development. Here we use naive hPSCs and human blastoids, 3D blastocyst models, to investigate the functional impact of DNMT3L on human naive pluripotency and preimplantation development. We demonstrate an essential role of DNMT3L in maintenance of DNA methylation patterns and chromatin states in naive hPSCs, and in trophectoderm cell fate induction and blastoid lineage identity. We further show that DNMT3L promotes reprogramming to naive pluripotency, and has integrated a hominoid-specific naive human pluripotency gene regulatory program involving evolutionarily recent transposable elements. Our work provides crucial insights into the molecular basis of human naive pluripotency and sheds light onto human preimplantation development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330591 | GEO | 2026/08/26

REPOSITORIES: GEO

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DNMT3L safeguards the epigenome and developmental potential of naive human pluripotent stem cells and blastoids

Project description:Studies of the catalytically inactive DNA methyltransferase Dnmt3l have mainly been limited to mice where Dnmt3l was shown to be essential for fertility, de novo DNA methylation in early embryos and maintenance of DNA methylation patterns in mouse pluripotent stem cells. In humans, recent work revealed that DNMT3L is the most highly enriched chromatin factor in naive pluripotent stem cells (hPSCs) compared with primed hPSCs. Naive hPSCs and stem cell-based human embryo models provide a unique opportunity to functionally the role of DNMT3L in human naive pluripotency and development. Here we use naive hPSCs and human blastoids, 3D blastocyst models, to investigate the functional impact of DNMT3L on human naive pluripotency and preimplantation development. We demonstrate an essential role of DNMT3L in maintenance of DNA methylation patterns and chromatin states in naive hPSCs, and in trophectoderm cell fate induction and blastoid lineage identity. We further show that DNMT3L promotes reprogramming to naive pluripotency, and has integrated a hominoid-specific naive human pluripotency gene regulatory program involving evolutionarily recent transposable elements. Our work provides crucial insights into the molecular basis of human naive pluripotency and sheds light on human preimplantation development.

2026-08-31 | PXD053638 | Pride

DNMT3L safeguards the epigenome and developmental potential of naive human pluripotent stem cells and blastoids

Project description:DNA methylation is essential for mammalian development. Studies of the catalytically inactive DNA methyltransferase Dnmt3l have mainly been limited to mice where Dnmt3l was shown to be essential for fertility, de novo DNA methylation in early embryos and maintenance of DNA methylation patterns in mouse pluripotent stem cells. Recent work revealed that DNMT3L is the most highly enriched chromatin factor in naive human pluripotent stem cells (hPSCs) compared with primed hPSCs. Stem cell-based human embryo models and naive hPSCs provide a unique opportunity to functionally dissect human developmental mechanisms. Here we use naive hPSCs and human blastoids, a 3D human blastocyst model, to investigate the functional impact of DNMT3L on human naive pluripotency and preimplantation development. We demonstrate an essential role of DNMT3L in trophectoderm cell fate induction, maintenance of DNA methylation patterns and chromatin states in naive hPSCs, and blastoid lineage identity. We further show that DNMT3L promotes reprogramming to naive pluripotency, and has integrated a hominoid-specific naive human pluripotency gene regulatory program involving evolutionary recent transposable elements. Therefore, DNMT3L plays conserved and hominoid-specific functions in human naive pluripotency and pre-implantation development.

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DNMT3L safeguards the epigenome and differentiation potential of human naive pluripotent stem cells and blastoids [CUT&Run]

Project description:Studies of the catalytically inactive DNA methyltransferase Dnmt3l have mainly been limited to mice where Dnmt3l was shown to be essential for fertility, de novo DNA methylation in early embryos and maintenance of DNA methylation patterns in mouse pluripotent stem cells. In humans, recent work revealed that DNMT3L is the most highly enriched chromatin factor in naive pluripotent stem cells (hPSCs) compared with primed hPSCs. Naive hPSCs and stem cell-based human embryo models provide a unique opportunity to functionally the role of DNMT3L in human naive pluripotent and development. Here we use naive hPSCs and human blastoids, 3D blastocyst models, to investigate the functional impact of DNMT3L on human naive pluripotency and preimplantation development. We demonstrate an essential role of DNMT3L in maintenance of DNA methylation patterns and chromatin states in naive hPSCs, and in trophectoderm cell fate induction and blastoid lineage identity. We further show that DNMT3L promotes reprogramming to naive pluripotency, and has integrated a hominoid-specific naive human pluripotency gene regulatory program involving evolutionarily recent transposable elements. Our work provides crucial insights into the molecular basis of human naive pluripotency and sheds light onto human preimplantation development.

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DNMT3L safeguards the epigenome and differentiation potential of human naive pluripotent stem cells and blastoids [Bisulfite-Seq]

Project description:Studies of the catalytically inactive DNA methyltransferase Dnmt3l have mainly been limited to mice where Dnmt3l was shown to be essential for fertility, de novo DNA methylation in early embryos and maintenance of DNA methylation patterns in mouse pluripotent stem cells. In humans, recent work revealed that DNMT3L is the most highly enriched chromatin factor in naive pluripotent stem cells (hPSCs) compared with primed hPSCs. Naive hPSCs and stem cell-based human embryo models provide a unique opportunity to functionally the role of DNMT3L in human naive pluripotent and development. Here we use naive hPSCs and human blastoids, 3D blastocyst models, to investigate the functional impact of DNMT3L on human naive pluripotency and preimplantation development. We demonstrate an essential role of DNMT3L in maintenance of DNA methylation patterns and chromatin states in naive hPSCs, and in trophectoderm cell fate induction and blastoid lineage identity. We further show that DNMT3L promotes reprogramming to naive pluripotency, and has integrated a hominoid-specific naive human pluripotency gene regulatory program involving evolutionarily recent transposable elements. Our work provides crucial insights into the molecular basis of human naive pluripotency and sheds light onto human preimplantation development.

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DNMT3L safeguards the epigenome and differentiation potential of human naive pluripotent stem cells and blastoids [Multiome]

Project description:Studies of the catalytically inactive DNA methyltransferase Dnmt3l have mainly been limited to mice where Dnmt3l was shown to be essential for fertility, de novo DNA methylation in early embryos and maintenance of DNA methylation patterns in mouse pluripotent stem cells. In humans, recent work revealed that DNMT3L is the most highly enriched chromatin factor in naive pluripotent stem cells (hPSCs) compared with primed hPSCs. Naive hPSCs and stem cell-based human embryo models provide a unique opportunity to functionally the role of DNMT3L in human naive pluripotent and development. Here we use naive hPSCs and human blastoids, 3D blastocyst models, to investigate the functional impact of DNMT3L on human naive pluripotency and preimplantation development. We demonstrate an essential role of DNMT3L in maintenance of DNA methylation patterns and chromatin states in naive hPSCs, and in trophectoderm cell fate induction and blastoid lineage identity. We further show that DNMT3L promotes reprogramming to naive pluripotency, and has integrated a hominoid-specific naive human pluripotency gene regulatory program involving evolutionarily recent transposable elements. Our work provides crucial insights into the molecular basis of human naive pluripotency and sheds light onto human preimplantation development.

2026-08-26 | GSE331498 | GEO

DNMT3L safeguards the epigenome and differentiation potential of human naive pluripotent stem cells and blastoids [RNA-Seq]

Project description:Studies of the catalytically inactive DNA methyltransferase Dnmt3l have mainly been limited to mice where Dnmt3l was shown to be essential for fertility, de novo DNA methylation in early embryos and maintenance of DNA methylation patterns in mouse pluripotent stem cells. In humans, recent work revealed that DNMT3L is the most highly enriched chromatin factor in naive pluripotent stem cells (hPSCs) compared with primed hPSCs. Naive hPSCs and stem cell-based human embryo models provide a unique opportunity to functionally the role of DNMT3L in human naive pluripotent and development. Here we use naive hPSCs and human blastoids, 3D blastocyst models, to investigate the functional impact of DNMT3L on human naive pluripotency and preimplantation development. We demonstrate an essential role of DNMT3L in maintenance of DNA methylation patterns and chromatin states in naive hPSCs, and in trophectoderm cell fate induction and blastoid lineage identity. We further show that DNMT3L promotes reprogramming to naive pluripotency, and has integrated a hominoid-specific naive human pluripotency gene regulatory program involving evolutionarily recent transposable elements. Our work provides crucial insights into the molecular basis of human naive pluripotency and sheds light onto human preimplantation development.

2026-08-26 | GSE270955 | GEO

Temporal activation of NR5A2 and RARγ induce functional human naïve pluripotent state via modulating TGFβ pathway

Project description:Rejuvenated primed human pluripotent stem cells, naïve cells, are accessible through the manipulating transcription factors, singaling pathways or a combination of both. However, there is a notable challenge in the functions of naïve hPSCs. Here, we show that the brief treatment with two chemical agonists (2a) of nuclear receptors NR5A2 and RARγ along with 2i and lif (2a2iL) is sufficient to induce naive pluripotency during the reprogramming of fibroblasts and pre-established hPSCs as well as the generation of new cell lines from preimplantation embryos. These cells manifested global naive-specific critera especially the contribution into the human-mouse chimeras. We demonstrated that TGF-β pathway activity is potentially critical for induction and maintenance of 2a2iL naive hPSCs. Consequently, transient activation of TGF-β resulted in generation of naive hPSCs in 2iL condition. These results represent a naive pluripotent state which is in a top point of developmental potential equivalent with preimplantation human embryo.

2018-07-03 | GSE116501 | GEO

Human Naive Pluripotency Attained by Transient Inhibition of mTor

Project description:Mouse embryonic stem cells (mESCs) are in naive pluripotency that represents the ground state of development, from which all cells in the mouse embryo are derived. In contrast, human embryonic stem cells (hESCs) are in a primed state of pluripotency with many different properties. Despite intense efforts to generate naive human pluripotent stem cells (hPSCs), it has not been possible to derive naive hPSCs without relying on transgene overexpression or chemicals. Here, we show that a transient treatment with Torin1, a selective inhibitor of mTOR, converted hPSCs from primed to naive pluripotency. The naive hPSCs were maintained in the same condition as mESCs in defined media with 2iLI (MEK inhibitor, GSK3b inhibitor, LIF and Insulin). Like mESCs, they exhibited high clonal efficiency, rapid cell proliferation, active mitochondrial respiration, X chromosome activation, DNA hypomethylation, and transcriptomes similar to those of human blastocysts than primed hESCs. Most importantly, the naive hPSCs significantly contributed to mouse embryos when transferred to mouse blastocysts. mTor inhibition induced nuclear translocation of TFE3, a critical transcription factor at the interplay of autophagy and pluripotency. TFE3 with mutated nuclear localization signal blocked the conversion from primed to naive pluripotency. It appears that by mimicking diapause at the cellular level, naive pluripotency in human can be readily attained from primed hPSCs, thus establishing the unified ground state of pluripotency in mammals.

2020-05-13 | GSE87452 | GEO

Human Naive Pluripotency Attained by Transient Inhibition of mTOR

2020-05-13 | GSE102031 | GEO

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Project description:Naive human pluripotent cells have been isolated in culture, but it remains unclear to what extent they resemble pluripotent cells in vivo. Here we present three lines of evidence indicating that naive pluripotent stem cells generated by small molecules share defining molecular signatures with the human preimplantation embryo. First, a comprehensive analysis of the transposcriptome reveals that naive human cells display a unique transposon expression profile of cleavage stage embryos. Second, induction of naive pluripotency is accompanied by a genome-wide depletion in DNA methylation that is reversible upon differentiation except at imprinted regions. Third, allele-specific analysis demonstrates that female naive cells exhibit an X chromosome signature of the human preimplantation embryo. However, when introduced into mouse embryos the naive cells failed to efficiently generate interspecies chimeras. Our work provides a set of molecular benchmarks for evaluating the developmental identity of distinct human pluripotent states captured in vitro.

2016-07-18 | GSE75868 | GEO

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