Open AccessRap1 regulates TIP60 function during fate transition between two-cell-like and pluripotent states
Author(s) -
Raymond Mario Barry,
Olivia Sacco,
Amel Mameri,
Martin Stojaspal,
William Kartsonis,
Priyal Shah,
Pablo De Ioannes,
Ctirad Hofr,
Jacques Côté,
Agnel Sfeir
Publication year - 2022
Publication title -
genes and development
Language(s) - English
Resource type - Journals
eISSN - 1549-5477
pISSN - 0890-9369
DOI - 10.1101/gad.349039.121
Subject(s) - biology , rap1 , telomere , microbiology and biotechnology , regulation of gene expression , gene , histone , histone acetyltransferase , genetics
In mammals, the conserved telomere binding protein Rap1 serves a diverse set of nontelomeric functions, including activation of the NF-kB signaling pathway, maintenance of metabolic function in vivo, and transcriptional regulation. Here, we uncover the mechanism by which Rap1 modulates gene expression. Using a separation-of-function allele, we show that Rap1 transcriptional regulation is largely independent of TRF2-mediated binding to telomeres and does not involve direct binding to genomic loci. Instead, Rap1 interacts with the TIP60/p400 complex and modulates its histone acetyltransferase activity. Notably, we show that deletion of Rap1 in mouse embryonic stem cells increases the fraction of two-cell-like cells. Specifically, Rap1 enhances the repressive activity of Tip60/p400 across a subset of two-cell-stage genes, including Zscan4 and the endogenous retrovirus MERVL. Preferential up-regulation of genes proximal to MERVL elements in Rap1-deficient settings implicates these endogenous retroviral elements in the derepression of proximal genes. Altogether, our study reveals an unprecedented link between Rap1 and the TIP60/p400 complex in the regulation of pluripotency.