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

SUMMARYTET1 maintains hypomethylation at bivalent promoters through its catalytic activity in embryonic stem cells (ESCs). However, whether and how TET1 exerts catalytic activity-independent functions in regulating bivalent genes is not well understood. Using a proteomics approach, we mapped the TET1 interactome in mouse ESCs and identified PSPC1 as a novel TET1 partner. Genome-wide location analysis reveals that PSPC1 functionally associates with TET1 and Polycomb repressive complex-2 (PRC2) complex. We establish that PSPC1 and TET1 repress, and Neat1, the PSPC1 cognate lncRNA, activates the bivalent gene expression. In ESCs, Neat1 tethers the TET1-PSPC1 pair with PRC2 at bivalent promoters. During the ESC-to-formative epiblast-like stem cell (EpiLC) transition, PSPC1 and TET1 promote PRC2 chromatin occupancy at bivalent gene promoters while restricting Neat1 functions in facilitating PRC2 binding to bivalent gene transcripts. Our study uncovers a novel TET1-PSPC1-Neat1 molecular axis that modulates PRC2 binding affinity to chromatin and bivalent gene transcripts in controlling stem cell bivalency.In BriefTET1 is a transcriptional repressor for bivalent genes in pluripotent stem cells, but its mechanistic action on stem cell bivalency is unclear. Huang et al. use proteomics and genetic approaches to reveal that catalytic activity-independent functions of TET1, coordinated with the paraspeckle components PSPC1 and its cognate lncRNA Neat1, dynamically regulates stem cell bivalency by modulating PRC2 binding affinity to chromatin and bivalent gene transcripts in pluripotent state transition.HighlightsThe TET1 interactome identifies PSPC1 as a novel partner in ESCsTET1 and PSPC1 repress bivalent genes by promoting PRC2 chromatin occupancyNeat1 facilitates bivalent gene activation by promoting PRC2 binding to their mRNAsNeat1 bridges the TET1-PSPC1 and PRC2 complexes in regulating bivalent gene transcription

Bivalent chromatin protects reversibly repressed genes from irreversible silencing

ABSTRACTBivalent chromatin is characterized by the simultaneous presence of H3K4me3 and H3K27me3, histone modifications generally associated with transcriptionally active and repressed chromatin, respectively. Prevalent in embryonic stem cells, bivalency is postulated to poise lineage-controlling developmental genes for rapid activation during embryogenesis while maintaining a transcriptionally repressed state in the absence of activation cues, but its function in development and disease remains a mystery. Here we show that bivalency does not poise genes for rapid activation but protects reversibly repressed genes from irreversible silencing. We find that H3K4me3 at bivalent gene promoters—a product of the underlying DNA sequence—persists in nearly all cell types irrespective of gene expression and confers protection from de novo DNA methylation. Accordingly, loss of H3K4me3 at bivalent promoters is strongly associated with aberrant hypermethylation and irreversible silencing in adult human cancers. Bivalency may thus represent a distinct regulatory mechanism for maintaining epigenetic plasticity.HIGHLIGHTSBivalent chromatin does not poise genes for rapid activationH3K4me3 at bivalent promoters is not instructive for transcription activationH3K4me3 at bivalent promoters protects reversibly repressed genes from de novo DNA methylationLoss of H3K4me3/bivalency is associated with aberrant DNA hypermethylation in cancer