Rap1 regulates TIP60 function during fate transition between two-cell-like and pluripotent states
| Autor: | Raymond Mario Barry, Olivia Sacco, Amel Mameri, Martin Stojaspal, William Kartsonis, Pooja Shah, Pablo De Ioannes, Ctirad Hofr, Jacques Côté, Agnel Sfeir |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Genes & Development. 36:313-330 |
| ISSN: | 1549-5477 0890-9369 |
| DOI: | 10.1101/gad.349039.121 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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