CTCF is a barrier for 2C-like reprogramming

Olbrich, Teresa; Vega-Sendino, María; Tillo, Desiree; Wu, Wei; Zolnerowich, Nicholas; Pavani, Raphael Souza; Tran, Andy D.; Domingo, Catherine N.; Franco, Mariajose; Markiewicz-Potoczny, Marta; Pegoraro, Gianluca; Fitzgerald, Peter; Kruhlak, Michael J.; Denchi, Eros Lazzerini; Nora, Elphège P.; Nussenzweig, André; Ruíz, Sergio

doi:10.1038/s41467-021-25072-x

Cited by 48 publications

(52 citation statements)

References 72 publications

(136 reference statements)

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“…In contrast, the swift attenuation of Dux and MERVL expression for two-cell stage exit is likely essential both in vitro and in vivo. Dux overexpression arrests embryos at the two- to four-cell stage ( Guo et al 2019 ), while prolonged Dux overexpression in ESCs causes DNA damage and apoptosis ( Olbrich et al 2021 ). Similarly, DUX4 derepression in muscle cells causes the human disease facioscapulohumeral muscular dystrophy (FSHD), characterized by up-regulation of DUX4 target genes, dsRNAs, TEs, and apoptosis ( Dixit et al 2007 ; Geng et al 2012 ; Shadle et al 2017 ).…”

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confidence: 99%

Nucleolar-based Dux repression is essential for embryonic two-cell stage exit

et al. 2022

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Upon fertilization, the mammalian embryo must switch from dependence on maternal transcripts to transcribing its own genome, and in mice this involves the transient up-regulation of MERVL transposons and MERVL-driven genes at the two-cell stage. The mechanisms and requirement for MERVL and two-cell (2C) gene up-regulation are poorly understood. Moreover, this MERVL-driven transcriptional program must be rapidly shut off to allow two-cell exit and developmental progression. Here, we report that robust ribosomal RNA (rRNA) synthesis and nucleolar maturation are essential for exit from the 2C state. 2C-like cells and two-cell embryos show similar immature nucleoli with altered structure and reduced rRNA output. We reveal that nucleolar disruption via blocking RNA polymerase I activity or preventing nucleolar phase separation enhances conversion to a 2C-like state in embryonic stem cells (ESCs) by detachment of the MERVL activator Dux from the nucleolar surface. In embryos, nucleolar disruption prevents proper nucleolar maturation and Dux silencing and leads to two- to four-cell arrest. Our findings reveal an intriguing link between rRNA synthesis, nucleolar maturation, and gene repression during early development.

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confidence: 99%

Nucleolar-based Dux repression is essential for embryonic two-cell stage exit

et al. 2022

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“…During the mESC to 2CLC transition, a lower TAD strength and TAD insulation have been observed [39]. Consistent with this is the disruption of chromatin organization by the depletion of CCCTC-binding factor (CTCF)/Cohesin or by culturing with CX-5461 upregulate Dux expression and promote a 2-cell-like program [13,14]. It is worth noting that the attenuation of H3K9me3 and H3K27me3 in CX-5461-treated cells is associated with the reinforcement of a repressed chromatin state [65].…”

Section: D Genome Conformationmentioning

confidence: 81%

“…These results indicate that epigenetic modification is important for the chromatin state change [67]. Chromatin relaxation facilitates the binding of transcription factors to the Dux locus, which might be the first step required to promote Dux expression [14,39]. The expression of DUX increases the active histone modifications and chromatin accessibility [9], and this positive feedback loop might be required to promote the 2C-like state (Figure 4).…”

Section: D Genome Conformationmentioning

confidence: 92%

“…A transcriptome analysis of mouse preimplantation embryos revealed that the activation of unique transcripts takes place at the 2-cell stage but is undetectable at any other stages. These transcripts include, but are not limited to, zinc finger and SCAN domain containing 4 (Zscan4) [9][10][11][12][13][14], zinc finger protein 352 (Zfp352) [9], 2-cell-stage, variable group, member 1/3 (Tcstv1/3) [9], predicted gene 4340 (Gm4340) [11], TD and POZ domain containing 1-5 (Tdpoz1-5) [14] and procollagen-proline, 2-oxoglutarate 4-dioxygenase, 2 of 13 alpha II polypeptide (P4ha2) [10], most of them able to generate chimaeric transcripts linked to murine endogenous retrovirus with leucine tRNA primer (MERVL) element. The MERVL-one class of endogenous retroviral elements (ERVs) and hundreds of genes driven by the 5 LTR of MERVL are upregulated specifically at the 2-cell stage.…”

Section: Introductionmentioning

confidence: 99%

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DUX: One Transcription Factor Controls 2-Cell-like Fate

Ren¹,

Gao²,

Mou³

et al. 2022

IJMS

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The double homeobox (Dux) gene, encoding a double homeobox transcription factor, is one of the key drivers of totipotency in mice. Recent studies showed Dux was temporally expressed at the 2-cell stage and acted as a transcriptional activator during zygotic genome activation (ZGA) in embryos. A similar activation occurs in mouse embryonic stem cells, giving rise to 2-cell-like cells (2CLCs). Though the molecular mechanism underlying this expanded 2CLC potency caused by Dux activation has been partially revealed, the regulation mechanisms controlling Dux expression remain elusive. Here, we discuss the latest advancements in the multiple levels of regulation of Dux expression, as well as Dux function in 2CLCs transition, aiming to provide a theoretical framework for understanding the mechanisms that regulate totipotency.

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“…Notably, the 2C-like transition recapitulates the transcriptomic features of the transition between totipotency and pluripotency of embryonic development[8; 9]. Thus, the 2C-like transition is currently a widely-used model for mechanistic exploration of cell-fate transition between totipotency and pluripotency[2; 3; 4; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30].…”

Section: Introductionmentioning

confidence: 99%

Zfp281 inhibits the pluripotent-to-totipotent state transition in mouse embryonic stem cells

Wen

Lin

et al. 2022

Preprint

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The cell-fate transition between pluripotent and totipotent states determines embryonic development and the first cell-lineage segregation. However, limited by the scarcity of totipotent embryos, regulators on this transition remain largely elusive. A novel model to study the transition has been recently established, named the 2-cell-like (2C-like) model. The 2C-like cells are rare totipotent-like cells in the mouse embryonic stem cell (mESC) culture. Pluripotent mESCs can spontaneously transit into and out of the 2C-like state. We previously dissected the transcriptional roadmap of the transition. In this study, we revealed that Zfp281 is a novel regulator for the pluripotent-to-totipotent transition in mESCs. Zfp281 is a transcriptional factor involved in the cell-fate transition. Our study shows that Zfp281 represses transcripts upregulated during the 2C-like transition via Tet1 and consequentially inhibits mESCs from transiting into the 2C-like state. Interestingly, we found that the inhibitory effect of Zfp281 on the 2C-like transition leads to an impaired 2C-like-transition ability in primed-state mESCs. Altogether, our study reveals a novel mediator for the pluripotent-to-totipotent state transition in mESCs and provides insights into the dynamic transcriptional control of the transition.

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CTCF is a barrier for 2C-like reprogramming

Cited by 48 publications

References 72 publications

Nucleolar-based Dux repression is essential for embryonic two-cell stage exit

Nucleolar-based Dux repression is essential for embryonic two-cell stage exit

DUX: One Transcription Factor Controls 2-Cell-like Fate

Zfp281 inhibits the pluripotent-to-totipotent state transition in mouse embryonic stem cells

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