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A TET1-PSPC1-Neat1 molecular axis modulates PRC2 functions in controlling stem cell bivalency

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

ORGANISM(S): Mus musculus

PROVIDER: GSE182443 | GEO | 2022/06/07

REPOSITORIES: GEO

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A TET1-PSPC1-Neat1 molecular axis modulates PRC2 functions in controlling stem cell bivalency.

Project description:TET1 maintains hypomethylation at bivalent promoters through its catalytic activity in embryonic stem cells (ESCs). However, TET1 catalytic activity-independent function in regulating bivalent genes is not well understood. Using a proteomics approach, we map the TET1 interactome in ESCs and identify PSPC1 as a TET1 partner. Genome-wide location analysis reveals that PSPC1 functionally associates with TET1 and Polycomb repressive complex-2 (PRC2). We establish that PSPC1 and TET1 repress, and the lncRNA Neat1 activates, bivalent gene expression. In ESCs, Neat1 is preferentially bound to PSPC1 alongside its PRC2 association at bivalent promoters. During the ESC-to-epiblast-like stem cell (EpiLC) transition, PSPC1 and TET1 maintain PRC2 chromatin occupancy at bivalent gene promoters, while Neat1 facilitates the activation of certain bivalent genes by promoting PRC2 binding to their mRNAs. Our study demonstrates a TET1-PSPC1-Neat1 molecular axis that modulates PRC2-binding affinity to chromatin and bivalent gene transcripts in controlling stem cell bivalency.

| S-EPMC9214724 | biostudies-literature

A TET1-PSPC1-Neat1 molecular axis modulates PRC2 functions in controlling stem cell bivalency [ChIP-seq]

Project description:The mammalian Ten-eleven translocation (TET) family proteins regulate the epigenome through catalytic activity (CA)-dependent and -independent functions. While catalytic activity of TETs has been intensely studied as DNA demethylation enzymes, little is known about their CA-independent function in early embryo development. Here we defined the CA-independent function of TET1 in naïve-to-formative pluripotent states transition. Using a proteomics method, we mapped the TET1 interactome and identified Paraspeckle component 1 (PSPC1) as a partner of TET1 for transcriptional repression at the bivalent genes in early development. Genome-wide location analysis revealed that PSPC1-bound regions largely overlap with TET1 and Polycomb repressive complex 2 (PRC2) subunits. Functional studies with genetic methods indicated that PSPC1 and TET1 repress, while lncRNA Neat1 activates the bivalent genes during their transcriptional activation. In embryonic stem cell (ESC) state, Neat1 tethers TET1, PSPC1, and PRC2 at promoters. During the ESCs to formative Epiblast like stem cells (EpiLCs) differentiation, PSPC1 and TET1 repress the PRC2 affinity to nascent mRNA transcripts of bivalent genes, while Neat1 facilitates PRC2 binding to those transcripts. Our study reveals a molecular mechanism by which proteins TET1 and PSPC1, and lncRNA Neat1 dynamically regulate gene transcription by modulating the PRC2 activity in pluripotent states transition.

2022-06-07 | GSE182442 | GEO

A TET1-PSPC1-Neat1 molecular axis modulates PRC2 functions in controlling stem cell bivalency [RNA-seq]

2022-06-07 | GSE182441 | GEO