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.

Institute of Biophysics of the Czech Academy of Sciences Scientific Incubator 612 65 Brno Czech Republic

LifeB Functional Genomics and Proteomics National Centre for Biomolecular Research Faculty of Science Masaryk University 625 00 Brno Czech Republic

Molecular Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York New York 10065 USA

Skirball Institute of Biomolecular Medicine Department of Biochemistry and Molecular Pharmacology New York University School of Medicine New York New York 10016 USA

Skirball Institute of Biomolecular Medicine Department of Cell Biology New York University School of Medicine New York New York 10016 USA

St Patrick Research Group in Basic Oncology; CHU de Québec Université Laval Research Center Oncology Division Laval University Cancer Research Center Quebec City Quebec G1R 3S3 Canada

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