A TRIM66/DAX1/Dux axis suppresses the totipotent 2-cell-like state in murine embryonic stem cells

Zuo, Feifei; Jiang, Junyi; Fu, Haipeng; Yan, Kun; Liefke, Robert; Zhang, Jing; Hong, Yaqiang; Liu, Nian; Wang, Zhanxin; Xi, Qiaoran

doi:10.1016/j.stem.2022.05.004

Cited by 19 publications

(26 citation statements)

References 73 publications

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“…Indeed, sustained activation of the 2C-associated transcriptional program induces developmental arrest with blastomeres at the 4C stage having a 2C transcriptional signature 10 . Silencing of the 2C transcriptional program involves redundant but rather independent mechanisms, including transcriptional repression of the Dux gene by TRIM66, the E3 ligase PIAS4 or SMCHD1 as well as physical recruitment of Dux loci to nucleolar heterochromatin [11][12][13][14] . Furthermore, MERVL repeats are transcriptionally silenced by the protein complex ZMYM2/LSD1 or the chromatin remodeler CAF-1 and post-transcriptionally by the RNA decay complex NEXT [15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

The homeobox transcription factor DUXBL controls exit from totipotency

Vega-Sendino

Olbrich

Stein

et al. 2022

Preprint

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Upon exit from the totipotent 2-cell (2C) embryo stage, the 2C-associated transcriptional program needs to be efficiently silenced. However, the molecular mechanisms involved in this process remain mostly unknown. Here, we demonstrate that the 2C-specific transcription factor DUX directly induces the expression of DUXBL to promote this silencing. Indeed, DUX expression in Duxbl-knockout ESC causes increased induction of the 2C-transcriptional program, whereas DUXBL overexpression impairs 2C-associated transcription. CUT&RUN analyses show that DUXBL gains accessibility to DUX-bound regions in DUX-induced ESC while it is unable to bind those regions in uninduced cells. Mechanistically, we determined that DUXBL interacts with TRIM24 and TRIM33, two members of the tripartite motif superfamily involved in gene silencing and co-localizes with them in nuclear foci upon DUX expression. Furthermore, DUXBL downregulation in mouse zygotes leads to a penetrant 2C-stage arrest. Our data reveals an unexpected role for DUXBL in controlling the exit from totipotency.

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Section: Introductionmentioning

confidence: 99%

The homeobox transcription factor DUXBL controls exit from totipotency

Vega-Sendino

Olbrich

Stein

et al. 2022

Preprint

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“…Otx2 , a member of the OTX family highly expressed in mouse blastocysts and ESCs, negatively regulated Dux , Zscan4c , MERVL, and other ZGA genes in mESCs ( Guo et al, 2021 ). Highly abundant TRIM66/DAX1 in mESCs served as a negative regulator of the 2C-like state through repressing Dux transcription ( Zuo et al, 2022 ). These factors may all be involved in the dissolution of the 2C-like state.…”

Section: Understanding the Totipotency State From Integrated Anglesmentioning

confidence: 99%

The regulation of totipotency transcription: Perspective from in vitro and in vivo totipotency

Liang

2022

Front. Cell Dev. Biol.

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Totipotency represents the highest developmental potency. By definition, totipotent stem cells are capable of giving rise to all embryonic and extraembryonic cell types. In mammalian embryos, totipotency occurs around the zygotic genome activation period, which is around the 2-cell stage in mouse embryo or the 4-to 8-cell stage in human embryo. Currently, with the development of in vitro totipotent-like models and the advances in small-scale genomic methods, an in-depth mechanistic understanding of the totipotency state and regulation was enabled. In this review, we explored and summarized the current views about totipotency from various angles, including genetic and epigenetic aspects. This will hopefully formulate a panoramic view of totipotency from the available research works until now. It can also help delineate the scaffold and formulate new hypotheses on totipotency for future research works.

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“…In conclusion, global DNA demethylation of zygotes in the early stages of development 28 , 29 , overexpression of embryogenesis-related genes after DNA demethylation 30 , and many studies show the administration of demethylation agents (mostly 5-Azacitidine (Aza)) leads to induction of stem cells, especially ICM and trophoblast stem cells 30 – 35 might be evidence to show the role of global DNA demethylation in the induction of totipotent stem cells. In addition, it has been shown that DNMTs could inhibit ZSCAN4 36 , 37 , a co-effector of DUX and totipotent stem cells 38 , 39 . DNMTs also regulate TERT and telomeres 40 which show a significant role of Dnmts in the totipotent state.…”

Section: Introductionmentioning

confidence: 99%

Reprogramming of fibroblast cells to totipotent state by DNA demethylation

Ghazimoradi

Hasegawa

Zolghadr

et al. 2023

Sci Rep

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Many attempts have been made to induce high-quality embryonic stem cells such as pluripotent stem cells and totipotent stem cells, but challenges remain to be overcome such as appropriate methods and sources. Demethylation of the genome after fertilization is an important step to initiate zygote gene activation, which can lead to the development of new embryos. Here, we tried to induce totipotent stem cells by mimicking DNA demethylation patterns of the embryo. Our data showed, after induction of DNA demethylation via chemicals or knockdown of Dnmts, cells positive for Nanog, and Cdx2 emerged. These cells could differentiate into the pluripotent and trophoblast lineage cells in-vitro. After transferring these cells to the uterus, they can implant and form embryo-like structures. Our study showed the importance of DNA demethylation roles in totipotent stem cell induction and a new and easy way to induce this cell type.

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A TRIM66/DAX1/Dux axis suppresses the totipotent 2-cell-like state in murine embryonic stem cells

Cited by 19 publications

References 73 publications

The homeobox transcription factor DUXBL controls exit from totipotency

The homeobox transcription factor DUXBL controls exit from totipotency

The regulation of totipotency transcription: Perspective from in vitro and in vivo totipotency

Reprogramming of fibroblast cells to totipotent state by DNA demethylation

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