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

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Authors

RAYMOND MARIO Barry SACCO Olivia MAMERI Amel STOJASPAL Martin KARTSONIS William SHAH Pooja DE IOANNES Pablo HOFR Ctirad CÔTÉ Jacques SFEIR Agnel

Year of publication 2022
Type Article in Periodical
Magazine / Source Genes & Development
MU Faculty or unit

Faculty of Science

Citation
Web http://genesdev.cshlp.org/content/early/2022/02/23/gad.349039.121.long
Doi http://dx.doi.org/10.1101/gad.349039.121
Keywords 2C-like; EPC1; MERVL; RAP1; TIP60; ZSCAN4; telomere
Description 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 upregulation 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.
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