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

Abstract

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.

Regulation of endogenous retroviruses in murine embryonic stem cells and early embryos

“…Unlike Zscan4, other proteins that help maintain telomere length are suppressors rather than activators of ERVs ( Figure 1C ). Telomere-associated proteins, such as Tin2 and Rap1, play a crucial role in silencing MERVL in ESCs ( Barry et al., 2022 ; Yin et al., 2022 ). These findings underscore the significance of telomere length and telomere-associated proteins in the regulation of ERV expression.…”

Tieing together loose ends: telomere instability in cancer and aging

“…Telomere erosion itself is also linked with marked alterations in the epigenetic state [94,[97][98][99]. For example, when telomere protection or telomere erosion are perturbed in mice, genome-wide transcriptional and epigenetic alterations ensue [82,[100][101][102][103][104][105][106][107][108]. Furthermore, during senescence, or upon the distruption of telomere maintenance or Trf1 function, associated changes in the chromatin landscape occur that are linked to the dysregulation of the chromatin modifying complex, Polycomb Repressive Complex 2 (PRC2) and/or to changes in histone or DNA methylation status [81,82,109].…”

The Role of the Histone Variant H2A.Z in Metazoan Development

“…A recent study compared the knockout of several different components in the p400–TIP60 complex in mESCs. The authors found that the individual knockout of TIP60, EPC1, DMAP1, or p400 ( Figure 4 ) produced different effects by up- or downregulating the expression of different subsets of genes [ 118 ]. Thus, the function of p400–TIP60 in depositing H2A.Z during different developmental stages remains unclear.…”