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SS18 regulates pluripotent-somatic transition through phase separation.

ABSTRACT: The transition from pluripotent to somatic states marks a critical event in mammalian development, but remains largely unresolved. Here we report the identification of SS18 as a regulator for pluripotent to somatic transition or PST by CRISPR-based whole genome screens. Mechanistically, SS18 forms microscopic condensates in nuclei through a C-terminal intrinsically disordered region (IDR) rich in tyrosine, which, once mutated, no longer form condensates nor rescue SS18^-/- defect in PST. Yet, the IDR alone is not sufficient to rescue the defect even though it can form condensates indistinguishable from the wild type protein. We further show that its N-terminal 70aa is required for PST by interacting with the Brg/Brahma-associated factor (BAF) complex, and remains functional even swapped onto unrelated IDRs or even an artificial 24 tyrosine polypeptide. Finally, we show that SS18 mediates BAF assembly through phase separation to regulate PST. These studies suggest that SS18 plays a role in the pluripotent to somatic interface and undergoes liquid-liquid phase separation through a unique tyrosine-based mechanism.

SUBMITTER: Kuang J

PROVIDER: S-EPMC8253816 | biostudies-literature |

REPOSITORIES: biostudies-literature

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SS18 regulates pluripotent-somatic transition through phase separation

Project description:The transition from pluripotent to somatic states marks a critical event in mammalian development, but remains largely unresolved. Here we report the identification of SS18 as a regulator for pluripotent to somatic transition or PST by CRISPR-based whole genome screens. Mechanistically, SS18 forms microscopic condensates in nuclei through a C-terminal intrinsically disordered region (IDR) rich in tyrosine, which, once mutated, no longer form condensates nor rescue SS18-/- defect in PST. Yet, the IDR alone is not sufficient to rescue the defect even though it can form condensates indistinguishable from the wild type protein. We further show that its N-terminal 70aa is required for PST by interacting with BAF complex, and remains functional even swapped onto unrelated IDRs or even an artificial 24 tyrosine polypeptide. Finally, we show that SS18 mediates BAF assembly through phase separation to regulate PST. These studies suggest that SS18 plays a role in the pluripotent to somatic interface and undergoes liquid-liquid phase separation through a unique tyrosine-based mechanism.

2021-05-23 | PXD026208 |

H3K27ac mediated SS18/BAFs relocation regulates JUN induced pluripotent-somatic transition.

Project description:BackgroundThe exit from pluripotency or pluripotent-somatic transition (PST) landmarks an event of early mammalian embryonic development, representing a model for cell fate transition.ResultsIn this study, using a robust JUN-induced PST within 8 h as a model, we investigate the chromatin accessibility dynamics (CAD) as well as the behaviors of corresponding chromatin remodeling complex SS18/BAFs, to probe the key events at the early stage of PST. Here, we report that, JUN triggers the open of 34661 chromatin sites within 4 h, accomplished with the activation of somatic genes, such as Anxa1, Fosl1. ChIP-seq data reveal a rapid relocation of SS18/BAFs from pluripotent loci to AP-1 associated ones. Consistently, the knockdown of Brg1, core component of BAF complexes, leads to failure in chromatin opening but not closing, resulting in delay for JUN induced PST. Notably, the direct interaction between SS18/BAFs and JUN-centric protein complexes is undetectable by IP-MS. Instead, we show that H3K27ac deposited by cJUN dependent process regulates SS18/BAFs complex to AP1-containing loci and facilitate chromatin opening and gene activation.ConclusionsThese results reveal a rapid transfer of chromatin remodeling complexes BAF from pluripotent to somatic loci during PST, revealing a simple mechanistic aspect of cell fate control.

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SS18 is a phase-separation protein relocating from pluripotent to somatic loci during mESC differentiation

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

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SS18/BAFs regulate chromatin accessibility dynamics during pluripotent-somatic transition

Project description:The exit from pluripotency or pluripotent-somatic transition (PST) landmarks an event of mammalian development, and is also a representative cell-fate transition model, but remains largely unresolved. Recently, we reported construction of robust JUN-induced PST completed in one cell cycle and whose dominant regulator SS18/BAFs (Brg1/Brahma-associated factors). However, the transition process in the chromatin architecture and the roles played by BAF are still unknown. Here we report the dynamic changes of chromatin accessibility during JUN-induced PST. Meanwhile, SS18/BAFs mediates PST process by relocating from pluripotent loci to AP-1 associated ones and once compromised, JUN fails to open chromatin and PST will be delayed. Furthermore, we show that the relocation of SS18/BAF partially relays on histone modification H3K27ac, instead of JUN-centric protein-protein interaction. These results reveal the orchestration of master transcription factor, epigenetic machine, and histone modification in the cell fate transition.

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