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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.

SUBMITTER: Barry RM 

PROVIDER: S-EPMC8973845 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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

Barry Raymond Mario RM   Sacco Olivia O   Mameri Amel A   Stojaspal Martin M   Kartsonis William W   Shah Pooja P   De Ioannes Pablo P   Hofr Ctirad C   Côté Jacques J   Sfeir Agnel A  

Genes & development 20220224 5-6


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  ...[more]

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