Chemical-induced chromatin remodeling reprograms mouse ESCs to totipotent-like stem cells

Yang, Mingzhu; Yu, Hanwen; Xiu, Yu; Liang, Shiqi; Hu, Yuanlang; Luo, Yuxin; Izsvák, Zsuzsanna; Sun, Chuanbo; Wang, Jichang

doi:10.1016/j.stem.2022.01.010

Cited by 88 publications

(98 citation statements)

References 95 publications

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“…At the 1-cell stage, Dot1l mRNA is found at comparable levels to that in oocytes, and the protein is detected in the nucleus ( Ooga et al, 2013 ). DOT1L protein is evicted from the nucleus at the 2-cell stage, a low level is present at the 4-cell stage, and there is a large increase in nuclear DOT1L in the blastocyst ( Ooga et al, 2013 ; Yang et al, 2022 ) ( Figure 1 ). Mirroring the DOT1L dynamics, H3K79me2 remains undetectable until the 4-cell stage, except for a sharp increase at the M phase of the cell cycle, followed by a manifold increase in the blastocyst ( Ooga et al, 2008 ; Cao et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Connecting the DOTs on Cell Identity

Wille

Sridharan

2022

Front. Cell Dev. Biol.

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DOT1-Like (DOT1L) is the sole methyltransferase of histone H3K79, a modification enriched mainly on the bodies of actively transcribing genes. DOT1L has been extensively studied in leukemia were some of the most frequent onco-fusion proteins contain portions of DOT1L associated factors that mislocalize H3K79 methylation and drive oncogenesis. However, the role of DOT1L in non-transformed, developmental contexts is less clear. Here we assess the known functional roles of DOT1L both in vitro cell culture and in vivo models of mammalian development. DOT1L is evicted during the 2-cell stage when cells are totipotent and massive epigenetic and transcriptional alterations occur. Embryonic stem cell lines that are derived from the blastocyst tolerate the loss of DOT1L, while the reduction of DOT1L protein levels or its catalytic activity greatly enhances somatic cell reprogramming to induced pluripotent stem cells. DOT1L knockout mice are embryonically lethal when organogenesis commences. We catalog the rapidly increasing studies of total and lineage specific knockout model systems that show that DOT1L is broadly required for differentiation. Reduced DOT1L activity is concomitant with increased developmental potential. Contrary to what would be expected of a modification that is associated with active transcription, loss of DOT1L activity results in more upregulated than downregulated genes. DOT1L also participates in various epigenetic networks that are both cell type and developmental stage specific. Taken together, the functions of DOT1L during development are pleiotropic and involve gene regulation at the locus specific and global levels.

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Section: Introductionmentioning

confidence: 99%

Connecting the DOTs on Cell Identity

Wille

Sridharan

2022

Front. Cell Dev. Biol.

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“…While our study was being submitted for publication, a study related to this work was published, 45 which reported an alternative chemical cocktail to support the generation of totipotent-like stem cells (TLSCs). Compared to our CPEC condition, the chemical cocktail reported by Yang et al 45 for generating TLSCs also included a DOT1L inhibitor, which further supports our finding that DOT1L inhibition is critical for totipotency regulation. Their chemical cocktail also contained other small molecules, such as A366 and AS8351.…”

Section: Discussionmentioning

confidence: 99%

Derivation of totipotent-like stem cells with blastocyst-like structure forming potential

Zhao

Ren

et al. 2022

Cell Res

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It is challenging to derive totipotent stem cells in vitro that functionally and molecularly resemble cells from totipotent embryos. Here, we report that a chemical cocktail enables the derivation of totipotent-like stem cells, designated as totipotent potential stem (TPS) cells, from 2-cell mouse embryos and extended pluripotent stem cells, and that these TPS cells can be stably maintained long term in vitro. TPS cells shared features with 2-cell mouse embryos in terms of totipotency markers, transcriptome, chromatin accessibility and DNA methylation patterns. In vivo chimera formation assays show that these cells have embryonic and extraembryonic developmental potentials at the single-cell level. Moreover, TPS cells can be induced into blastocyst-like structures resembling preimplantation mouse blastocysts. Mechanistically, inhibition of HDAC1/2 and DOT1L activity and activation of RARγ signaling are important for inducing and maintaining totipotent features of TPS cells. Our study opens up a new path toward fully capturing totipotent stem cells in vitro.

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“…Succinate accumulation would result in a global decrease in the activity of all 3 TET isoforms, resembling those of a TET triple KO, already shown to induce the 2C phenotype 36 . The methylation landscape of histones, especially H3, is also highly dynamic both in vivo, at the time of the zygote genome activation (ZGA) that takes place at the 2C-stage, and in the 2CLC conversion with remodeling of H3K4me3, H3K9me3 and H3K27me3 [58][59][60] (extensively reviewed in 61 ). Similarly to the situation with the TETs, the action of HDM on the loss or acquisition of 2C-like features in vitro is complex, as loss of KDM1a (lysine demethylase 1a) is shown to promote the expression of Zscan4 and MUERVL 62 whereas loss of KDM5a and b decreases the expression of the markers and blocks the ZGA in vivo 63 .…”

Section: Discussionmentioning

confidence: 99%

A critical role for heme synthesis and succinate in the regulation of pluripotent states transitions

Detraux

Caruso

Feller

et al. 2022

Preprint

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Using embryonic stem cells (ESCs) in regenerative medicine or in disease modeling requires a complete understanding of these cells. Two main distinct developmental states of ESCs have been stabilized in vitro, a naïve pre-implantation stage and a primed post-implantation stage. Based on two recently published CRISPR-Cas9 knockout functional screens, we show here that the exit of the naïve state is impaired upon heme biosynthesis pathway blockade, linked to the incapacity to activate MAPK- and TGFβ-dependent signaling pathways. In addition, heme synthesis inhibition promotes the acquisition of 2 cell-like cells in a heme-independent manner caused by a mitochondrial succinate accumulation and leakage out of the cell. We further demonstrate that extra-cellular succinate acts as a paracrine/autocrine signal, able to trigger the 2C-like reprogramming through the activation of its plasma membrane receptor, SUCNR1. Overall, this study unveils a new mechanism underlying the maintenance of pluripotency under the control of heme synthesis.

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Chemical-induced chromatin remodeling reprograms mouse ESCs to totipotent-like stem cells

Cited by 88 publications

References 95 publications

Connecting the DOTs on Cell Identity

Connecting the DOTs on Cell Identity

Derivation of totipotent-like stem cells with blastocyst-like structure forming potential

A critical role for heme synthesis and succinate in the regulation of pluripotent states transitions

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