Rap1 regulates TIP60 function during fate transition between two-cell-like and pluripotent states

Area of Science:

• Molecular Biology
• Epigenetics
• Stem Cell Biology

Background:

• Rap1 is a conserved telomere-binding protein with known non-telomeric roles, including NF-kB pathway activation and metabolic regulation.
• The precise mechanisms by which Rap1 influences transcriptional regulation are not fully understood.

Purpose of the Study:

• To elucidate the mechanism of Rap1-mediated gene expression modulation.
• To investigate the role of Rap1 in regulating pluripotency and two-cell-like cell states.

Main Methods:

• Utilized a separation-of-function Rap1 allele in mouse models.
• Investigated Rap1 interactions with the TIP60/p400 complex and its histone acetyltransferase activity.
• Analyzed gene expression changes in Rap1-deficient mouse embryonic stem cells, focusing on two-cell-stage genes and endogenous retroviruses.

Main Results:

• Rap1's transcriptional regulatory function is independent of telomere binding and direct genomic interactions.
• Rap1 interacts with and modulates the histone acetyltransferase activity of the TIP60/p400 complex.
• Rap1 deletion in mouse embryonic stem cells increases the proportion of two-cell-like cells, with Rap1 enhancing repression of genes like Zscan4 and MERVL.

Conclusions:

• Rap1 regulates gene expression through the TIP60/p400 complex, independent of its telomeric functions.
• Rap1 plays a critical role in suppressing two-cell-like gene expression and maintaining pluripotency.
• Endogenous retroviral elements like MERVL may contribute to the derepression of proximal genes in Rap1-deficient cells.