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The homeobox transcription factor DUXBL controls exit from the totipotent 2C state [Cut&Run]

ABSTRACT: 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 determined that the 2C-specific transcription factor DUX directly induced the expression of DUXBL to promote this silencing. CUT&RUN analysis revealed that DUXBL gained accessibility to DUX-bound regions in DUX-induced ESC while it was unable to bind those regions in uninduced cells. Importantly, DUX expression in Duxbl-knockout ESC caused increased induction of the 2C-transcriptional program, whereas DUXBL overexpression impaired 2C-associated transcription. Mechanistically, we determined that DUXBL interacted with TRIM24 and TRIM33, two members of the tripartite motif superfamily involved in gene silencing, and co-localized with them in nuclear condensates upon DUX expression. Importantly, DUXBL downregulation in mouse zygotes led to a penetrant 2C-stage arrest. Our data revealed an unexpected role for DUXBL in controlling the exit from totipotency.

ORGANISM(S): Mus musculus

PROVIDER: GSE210890 | GEO | 2023/12/06

REPOSITORIES: GEO

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The homeobox transcription factor DUXBL controls exit from the totipotent 2C state [RNA-seq]

Project description: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 determined that the 2C-specific transcription factor DUX directly induced the expression of DUXBL to promote this silencing. CUT&RUN analysis revealed that DUXBL gained accessibility to DUX-bound regions in DUX-induced ESC while it was unable to bind those regions in uninduced cells. Importantly, DUX expression in Duxbl-knockout ESC caused increased induction of the 2C-transcriptional program, whereas DUXBL overexpression impaired 2C-associated transcription. Mechanistically, we determined that DUXBL interacted with TRIM24 and TRIM33, two members of the tripartite motif superfamily involved in gene silencing, and co-localized with them in nuclear condensates upon DUX expression. Importantly, DUXBL downregulation in mouse zygotes led to a penetrant 2C-stage arrest. Our data revealed an unexpected role for DUXBL in controlling the exit from totipotency.

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The homeobox transcription factor DUXBL controls exit from totipotency

Project description:In mice, exit from the totipotent 2-cell (2C) embryo stage requires silencing of the 2C-associated transcriptional program. However, the molecular mechanisms involved in this process remain poorly understood. Here, we demonstrate that the 2C-specific transcription factor DUX mediates an essential negative feedback loop by inducing the expression of DUXBL to promote this silencing.We show that DUXBL gains accessibility to DUX-bound regions specifically upon DUX expression.Furthermore, we determine that DUXBL interacts with TRIM24 and TRIM33, members of the tripartite motif superfamily involved in gene silencing and co-localizes with them in nuclear foci upon DUX expression. Importantly, DUXBL overexpression impairs 2C-associated transcription, whereas Duxbl inactivation in ESC increases DUX-dependent induction of the 2C-transcriptional program. Consequently, DUXBL deficiency in embryos results in sustained expression of 2C-associated transcripts, leading to early developmental arrest.Our study identifies DUXBL as an essential regulator of totipotency exit enabling the first divergence of cell fates.

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Duxbl-mediated suppression of ZGA drives totipotency to pluripotency transition in mice III

Project description:In mammalian embryos, Dux transcription factors (TF) drive a cleavage stage-specific transcriptional burst associated with zygotic genome activation (ZGA) during which hundreds of genes and endogenous retroviral (ERV) elements are transiently expressed. In mice, ZGA begins in late 1-cell (1C) embryos and is shut down within hours at the late 2-cell (2C) to 4-cell (4C) stage. While this transition is accompanied by the loss of totipotency, it is not clear whether shutdown of Dux-induced ZGA is required for this process and how ZGA is terminated. Here, we reveal an essential negative feedback axis by which the Dux family member Duxbl terminates Dux-induced ZGA from the mid 2C stage onward by direct suppression of genomic Dux target loci. Consequently, Duxbl inactivation results in sustained expression of Dux-induced ZGA leading to 4C arrest. Our study reveals the Dux/Duxbl axis that determines the timing of totipotency exit enabling the very first divergence of cell fates.

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Duxbl-mediated suppression of ZGA drives totipotency to pluripotency transition in mice II

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Zfp352 over expression chip-seq result

Project description:Previous study has determined Dux regulates 2CLC trancriptome via binding and activating MERVL,but the mechanism about the change happned during the 2C-exit process are rarely determined.In this study,we try to illustrate how ZFP352 binds genome location to regulate its downstream trancriptome and 2C-exit process.And make some conclusion and hypothesis about ZFP352 co-binding and interact with other trancription factor:Dux,etc to regulate 2C-exit.

2023-06-01 | GSE202158 | GEO

The homeobox transcription factor DUXBL controls exit from the totipotent 2C state

Project description:The homeobox transcription factor DUXBL controls exit from the totipotent 2C state

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Global analysis of expression upon RNA Pol I inhibition (iPol I) in ESCs

Project description:Immediately following fertilisation, the genomes of mammalian embryos undergo extensive reprogramming to generate a totipotent zygote with the capacity to form the entire developing organism and associated extraembryonic tissues. The embryo must also switch from dependence on maternal transcripts to transcribing from its own genome, and is accompanied in mice by rapid and transient upregulation of MERVL transposons and MERVL-driven genes at the 2-cell stage. The mechanisms and requirement for MERVL and 2-cell (2C) gene upregulation are poorly understood. Moreover, this program must be rapidly shut off upon 2C exit and developmental progression. Here, we report that robust ribosomal RNA synthesis and nucleolar integrity are essential for exit from the 2C state. 2-cell embryos and 2C-like cells show immature nucleoli with altered structure and reduced function, and we reveal that nucleolar disruption induces conversion to the 2C-like state in ESCs. Mechanistically, the 2C/MERVL activator Dux is held in perinucleolar chromatin in ESCs and released into the nucleoplasm upon nucleolar disruption or direct inhibition of nucleolar phase separation, leading to its rapid upregulation. In embryos, nucleolar disruption prevents proper Dux silencing and leads to 2-4 cell arrest. Our findings reveal an intriguing link between rRNA synthesis, nucleolar maturation and gene repression during early development.

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DPPA2/4 and SUMO E3 ligase PIAS4 opposingly regulate the emergence of 2C-like cells and zygotic transcriptional program

Project description:The molecular mechanism controlling the zygotic genome activation (ZGA) in mammals remains poorly understood. The 2C-like cells spontaneously emerging from cultures of mouse embryonic stem cells (ESCs) share some key transcriptional and epigenetic programs with 2-cell stage embryos. By studying the transition of ESCs into 2C-like cells, we identified Dppa2/4 as important regulators controlling zygotic transcriptional program through directly upregulating the expression of Dux. In addition, we found that DPPA2 protein is sumoylated and its activity is negatively regulated by Sumo E3 ligase PIAS4. PIAS4 is downregulated during zygotic genome activation process and during transitioning of ESCs into 2C-like cells. Depleting Pias4 or overexpressing Dppa2/4 is sufficient to upregulateactivate 2C-like transcriptional program, while depleting Dppa2/4 or forced expression of PIAS4 or Sumo2-Dppa2 inhibits 2C-like transcriptional program. Furthermore, ectopic expression of Pias4 or Sumo2-Dppa2 impairs early mouse embryo development. In summary, our study identifies key molecular rivals consisting of transcription factors and a Sumo2 E3 ligase that regulate the transition of ESCs into 2C-like cells and zygotic transcriptional program upstream of Dux.

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Protein interactors of Duxbl in early mouse development

Project description:Duxbl is a member of the DUX (double homeobox) family of transcription factors with roles in embryonic development. This project aimed at identification of protein interactors of Duxbl. Following IP of flag-tagged exogenous Duxbl or EV, proteins were trypsin digested with S-traps. Following IP of endogenous Duxbl or IP with non-specific IgG, proteins were subjected to gel separation and in-gel trypsin digestion. All pulldowns were performed in biological replicate. Samples were run on either a Fusion tribrid (exogenous) or an Exploris 480 hydbrid (endogenous). Data were searched in PD 2.4 using the mouse database from Uniprot.

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