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

Area of Science:

• Stem cell biology
• Epigenetics
• Molecular biology

Background:

• TET1's role in hypomethylation at bivalent promoters is known, but its catalytic-independent functions are unclear.
• Bivalent genes are crucial for stem cell pluripotency and differentiation.
• Understanding regulators of bivalent genes is key to controlling cell fate.

Purpose of the Study:

• To identify TET1-interacting proteins and elucidate TET1's catalytic-independent functions.
• To investigate the roles of TET1, PSPC1, and Neat1 in regulating bivalent genes.
• To understand the molecular mechanisms controlling stem cell bivalency during differentiation.

Main Methods:

• Proteomics to map the TET1 interactome in embryonic stem cells (ESCs).
• Genome-wide location analysis to assess functional associations of PSPC1 with TET1 and PRC2.
• Analysis of gene expression and protein-RNA interactions during ESC to epiblast-like stem cell (EpiLC) transition.

Main Results:

• PSPC1 was identified as a novel TET1-interacting protein.
• PSPC1 and TET1 were found to repress bivalent gene expression, while Neat1 activates it.
• A TET1-PSPC1-Neat1 axis was demonstrated to modulate PRC2 binding to chromatin and mRNA, controlling bivalent gene expression.

Conclusions:

• PSPC1 is a functional partner of TET1 and PRC2 in regulating bivalent genes.
• The TET1-PSPC1-Neat1 complex plays a critical role in maintaining stem cell bivalency.
• This axis is essential for regulating gene expression during the ESC to EpiLC transition.