Stage-specific H3K9me3 occupancy ensures retrotransposon silencing in human pre-implantation embryos

Xu, Ruimin; Li, Sen; Wu, Qiu Liang; Li, Chong; Jiang, Man-Xi; Гуо, Лэй; Mo, Chen; Yang, Lingyue; Dong, Xin; Wang, Hong; Wang, Chenfei; Liu, Xiaoyu; Ou, Xiang‐Hong; Gao, Shaorong

doi:10.1016/j.stem.2022.06.001

Cited by 57 publications

(55 citation statements)

References 97 publications

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“…During ZGA, MERVL elements undergo extensive demethylation allowing LTRs to act as alternative promoters of 2C-associated protein-coding genes. Recent results have unveiled an epigenetic switch from DNA methylation to H3K9me3 deposition to regulate retrotransposon expression including MERVL elements 44,47 . Interestingly, DUX may contribute to the establishment of H3K9me3 regions as Dux -deficient embryos showed a significant reduction of H3K9me3 deposition 44 .…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

The homeobox transcription factor DUXBL controls exit from totipotency

Vega-Sendino

Olbrich

Stein

et al. 2022

Preprint

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“…In addition to MERVL, LINE-1 element transcription is observed most in a 2C embryo ( Jachowicz et al, 2017 ), which can function as a nuclear RNA scaffold to recruit the KAP1/nucleolin (NCL) complex to repress Dux in mESCs and pre-implantation mouse embryos ( Percharde et al, 2018 ). In early human embryos, hominoid-specific retrotransposon SINE-VNTR-Alu (SVA) elements are activated by H3K9me3 reprogramming, leading to activation of major ZGA gene expression ( Xu R. et al, 2022 ; Yu et al, 2022 ).…”

Section: Transcriptional Regulation Of the Totipotency Statementioning

confidence: 99%

“…It was found that incomplete depletion of H3K9me3 was a key reason underlying the arrest of somatic cloned embryos at the ZGA stage ( Matoba et al, 2014 ; Liu et al, 2016 ), and abnormal enrichment of H3K9me3 also severely hindered pre-implantation embryonic development in mice ( Burton et al, 2020 ). The correct establishment of H3K9me3 modifications on ERVs was recently found to be depending on Dux ( Xu R. et al, 2022 ). At the human 8C stage, H3K9me3 was reprogrammed on homology-specific retrotransposons of SVA (SINE-VNTR-Alu elements), remodeling the enhancer function of SVA to promote totipotent gene expression ( Yu et al, 2022 ).…”

Section: Epigenetic Regulation Of Totipotencymentioning

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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“…Importantly, the stage-specific activation of retrotransposons depends on precise epigenetic regulation during early human development (Xu et al, 2022;Yu et al, 2022). Recently, exploiting low-input ChIP-seq techniques, Xu et al and Yu et al independently discovered the significance of the stage-specific TE associated H3K9me3 landscape in human pre-implantation embryos (Xu et al, 2022;Yu et al, 2022).…”

Section: Retrotransposons In Early Human Developmentmentioning

confidence: 99%