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Lysosomal catabolic activity governs the exit of the murine totipotent 2-cell state by silencing early-embryonic retrotransposons [CUT&Tag]

ABSTRACT: During the development in mouse early embryos, a subset of retrotransposons and genes are transiently expressed in the totipotent 2-cell embryos. These 2-cell-embryo-asscoiated (referred to as 2C) transcripts rapidly shut down their expression beyond the late 2-cell stage of embryos, and this timely shutdown governs the embryo to exit from the 2-cell stage. However, mechanisms regulating this wave of shutdown are not fully understood. In this study, we established a novel connection between lysosomal catabolic activity and 2C transcripts in regulating the exit of totipotent 2-cell state by using both in vitro 2-cell-like cells model and mouse embryos. Our results showed that the activation of lysosomal catabolism in mouse embryos governed the embryo to exit from the 2-cell state by suppressing the expression of 2C transcripts. Mechanistically, we found that lysosomal catabolic activity modulated 2C transcripts by inactivating transcriptional factors Tfe3/Tfeb and abolishing their transcriptional activation on 2C retrotransposons, MERVL/MT2-Mm. Collectively, our study elucidates the function of lysosomal activity in orchestrating transcriptomic landscape and early development in mouse embryos and reveals an unanticipated layer of transcriptional control on early-embryonic retrotransposons from lysosomal signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE247081 | GEO | 2024/08/25

REPOSITORIES: GEO

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Lysosomal catabolic activity governs the exit of the murine totipotent 2-cell state by silencing early-embryonic retrotransposons [RNA-seq]

Project description:During the development in mouse early embryos, a subset of retrotransposons and genes are transiently expressed in the totipotent 2-cell embryos. These 2-cell-embryo-asscoiated (referred to as 2C) transcripts rapidly shut down their expression beyond the late 2-cell stage of embryos, and this timely shutdown governs the embryo to exit from the 2-cell stage. However, mechanisms regulating this wave of shutdown are not fully understood. In this study, we established a novel connection between lysosomal catabolic activity and 2C transcripts in regulating the exit of totipotent 2-cell state by using both in vitro 2-cell-like cells model and mouse embryos. Our results showed that the activation of lysosomal catabolism in mouse embryos governed the embryo to exit from the 2-cell state by suppressing the expression of 2C transcripts. Mechanistically, we found that lysosomal catabolic activity modulated 2C transcripts by inactivating transcriptional factors Tfe3/Tfeb and abolishing their transcriptional activation on 2C retrotransposons, MERVL/MT2-Mm. Collectively, our study elucidates the function of lysosomal activity in orchestrating transcriptomic landscape and early development in mouse embryos and reveals an unanticipated layer of transcriptional control on early-embryonic retrotransposons from lysosomal signaling.

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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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Lysosomal catabolic activity governs the exit of the murine totipotent 2-cell state by silencing early-embryonic retrotransposons

Project description:Lysosomal catabolic activity governs the exit of the murine totipotent 2-cell state by silencing early-embryonic retrotransposons

| PRJNA1036191 | ENA

Lysosomal catabolic activity governs the exit of the murine totipotent 2-cell state by silencing early-embryonic retrotransposons [RNA-seq]

Project description:Lysosomal catabolic activity governs the exit of the murine totipotent 2-cell state by silencing early-embryonic retrotransposons [RNA-seq]

| PRJNA1036202 | ENA

Lysosomal catabolic activity governs the exit of the murine totipotent 2-cell state by silencing early-embryonic retrotransposons [CUT&Tag]

Project description:Lysosomal catabolic activity governs the exit of the murine totipotent 2-cell state by silencing early-embryonic retrotransposons [CUT&Tag]

| PRJNA1036201 | ENA

RNA-seq of control siRNA, p150 siRNA and p60 siRNA transfected mES cells

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