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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE247083 | 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.

2024-08-25 | GSE247082 | GEO

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

2024-08-25 | GSE247081 | GEO

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 [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

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

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-05 | GSE210892 | GEO

Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly.

Project description:Mammalian cells can acquire exogenous amino acids through endocytosis and lysosomal catabolism of extracellular proteins. In amino acid-replete environments, nutritional utilization of extracellular proteins is suppressed by the amino acid sensor mechanistic target of rapamycin complex 1 (mTORC1) through an unknown process. Here, we show that mTORC1 blocks lysosomal degradation of extracellular proteins by suppressing V-ATPase-mediated acidification of lysosomes. When mTORC1 is active, peripheral V-ATPase V1 domains reside in the cytosol where they are stabilized by association with the chaperonin TRiC. Consequently, most lysosomes display low catabolic activity. When mTORC1 activity declines, V-ATPase V1 domains move to membrane-integral V-ATPase Vo domains at lysosomes to assemble active proton pumps. The resulting drop in luminal pH increases protease activity and degradation of protein contents throughout the lysosomal population. These results uncover a principle by which cells rapidly respond to changes in their nutrient environment by mobilizing the latent catabolic capacity of lysosomes.

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Totipotent embryonic stem cells arise in ground-state culture conditions.

Project description:Embryonic stem cells (ESCs) are derived from mammalian embryos during the transition from totipotency, when individual blastomeres can make all lineages, to pluripotency, when they are competent to make only embryonic lineages. ESCs maintained with inhibitors of MEK and GSK3 (2i) are thought to represent an embryonically restricted ground state. However, we observed heterogeneous expression of the extraembryonic endoderm marker Hex in 2i-cultured embryos, suggesting that 2i blocked development prior to epiblast commitment. Similarly, 2i ESC cultures were heterogeneous and contained a Hex-positive fraction primed to differentiate into trophoblast and extraembryonic endoderm. Single Hex-positive ESCs coexpressed epiblast and extraembryonic genes and contributed to all lineages in chimeras. The cytokine LIF, necessary for ESC self-renewal, supported the expansion of this population but did not directly support Nanog-positive epiblast-like ESCs. Thus, 2i and LIF support a totipotent state comparable to early embryonic cells that coexpress embryonic and extraembryonic determinants.

| S-EPMC3701323 | biostudies-literature

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.

2023-12-06 | GSE210891 | GEO