Rap1 regulates TIP60 function during fate transition between two-cell-like and pluripotent states.
Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, 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.
LifeB, Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic.
Skirball Institute of Biomolecular Medicine, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Institute of Biophysics of the Czech Academy of Sciences, Scientific Incubator, 612 65 Brno, Czech Republic.
- Published Article
Genes & development
- Publication Date
Mar 01, 2022
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. © 2022 Barry et al.; Published by Cold Spring Harbor Laboratory Press.
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This record was last updated on 06/16/2022 and may not reflect the most current and accurate biomedical/scientific data available from NLM.
The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/35210222