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Recruitment of TRIM33 to cell-context specific PML nuclear bodies regulates Nodal signaling in mESCs

ABSTRACT: TRIM33 is a chromatin reader required for mesendoderm differentiation upon activation of Nodal signaling. But, its role in mESCs is still elusive. Here, we found that TRIM33 co-localizes with promyelocytic leukemia nuclear bodies (PML NBs) specifically in mESCs to mediate Nodal signaling-directed transcription of Lefty1/2. We showed that TRIM33 puncta formation in mESCs depends on PML and specific assembly of PML NBs. Moreover, TRIM33 and PML co-regulate Lefty1/2 expression in mESCs. In addition, both PML and mESCs-specific PML NBs are required for TRIM33 recruitment at Lefty1/2 loci. Remarkably, PML NBs directly associate with the Lefty1/2 loci in mESCs. Finally, a TurboID proximity labeling experiment confirmed that TRIM33 is highly enriched in the mESCs-specific PML NBs. Thus, our study provides the mechanistic insight about TRIM33 condensate in regulating Nodal signaling-directed transcription in mESCs, it also reveals that PML NBs recruit distinct sets of client proteins in cell context dependent manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE199738 | GEO | 2022/12/08

REPOSITORIES: GEO

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PML nuclear bodies form a regulatory hub via liquid-liquid phase separation for TRIM33 control of Lefty1/2 genes in mouse embryonic stem cells [RNA-seq]

Project description:TRIM33 is a chromatin reader required for nodal signaling during mesendoderm differentiation, although differences in its function between mouse embryonic stem cells (mESCs) and differentiated mesendoderm cells are unknown. Here, we found that TRIM33 co-condenses with PML nuclear bodies (NBs) via liquid-liquid phase separation specifically in mESCs to mediate nodal signaling-directed transcription of Lefty1/2. Our findings show that TRIM33 puncta formation depends on the presence of PML NBs. TurboID proximity labeling further revealed that PML NBs recruit distinct sets of client proteins in NaAsO2-treated, untreated mESCs, and differentiated cells. TRIM33 and PML co-regulate Lefty1/2 expression, while PML NBs directly associate with the Lefty1/2 loci and regulate a gene cluster that includes Lefty1/2 loci specifically in mESCs. Moreover, TRIM33 association with chromatin depends on PML NBs. Thus, PML NBs serve as a hub for transcriptional regulation of Lefty1/2 by TRIM33 and other pluripotency factors in mESCs.

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2023-01-10 | PXD037432 | Pride

Unbiased in vivo exploration of nuclear bodies-enhanced sumoylation reveals that PML orchestrates embryonic stem cell fate (II)

Project description:Membrane-less organelles are condensates formed by phase separation whose functions often remain enigmatic. Upon oxidative stress, PML scaffolds Nuclear Bodies (NBs) to regulate senescence or metabolic adaptation, but their role in pluripotency remains elusive. Here we establish that PML is required for basal SUMO2/3 conjugation in mESCs and oxidative stress-driven sumoylation in mESCs or in vivo. PML NBs create an oxidationprotective environment for UBC9-driven SUMO2/3 conjugation of PML partners, often followed by their poly-ubiquitination and degradation. Differential in vivo proteomics identified several members of the KAP1 complex as PML NB-dependent SUMO2-targets. The latter drives functional activation of this key epigenetic repressor. Accordingly, Pml-/- mESCs reexpress transposable elements and display features of totipotent-like cells, a process further enforced by PML-controlled SUMO2-conjugation of DPPA2. Finally, PML is required for adaptive stress responses in mESCs. Collectively, PML orchestrates mESC fate through SUMO2-conjugation of key transcriptional or epigenetic regulators, raising new mechanistic hypotheses about PML roles in normal or cancer stem cells.

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Unbiased in vivo exploration of nuclear bodies-enhanced sumoylation reveals that PML orchestrates embryonic stem cell fate

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Project description:Recruitment of TRIM33 to cell-context specific PML nuclear bodies regulates Nodal signaling in mESCs

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PML Nuclear Bodies are stress-responsive sumoylation/degradation compartments regulating KAP1 silencing function in embryonic stem cells

Project description:PML drives the assembly of PML Nuclear Bodies (NBs), where it recruits many serendipitously-identified proteins, including the SUMO-E2 enzyme UBC9. Interferons, arsenic or oxidative stress, all enhance NB-formation. Here demonstrate that PML is required for efficient basal sumoylation in mouse embryonic stem cells (mESCs) and immediate stress-responsive sumoylation in mouse liver or Acute Promyelocytic Leukemia (APL). Biochemically, PML NBs confer an oxidation-protective environment for the redox-sensitive UBC9 activity, which, together with enzyme/target concentration/immobilization, favors processive SUMO2/3 conjugation. Accordingly, PML-facilitated sumoylation is accompanied by ubiquitination and degradation of some targets. In vivo proteomic analysis of SUMO2 conjugates in APL identified therapy-responsive targets, among which the prominent KAP1 complex of epigenetic regulators. In mESCs, PML is required for SUMO-dependent KAP1 repressive activity and for the resulting silencing of transposable elements and 2-cell-like genes. The ES status is further regulated by a PML-facilitated repressive sumoylation of the Dppa2 zygote genome activation driver. These findings establish the biochemical function of PML NBs in vivo and unveiling an unsuspected epigenetic control of key ESC targets by PML.

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