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

Authors
  • Barry, Raymond Mario1, 2
  • Sacco, Olivia2
  • Mameri, Amel3
  • Stojaspal, Martin1, 4
  • Kartsonis, William1
  • Shah, Pooja1
  • De Ioannes, Pablo5
  • Hofr, Ctirad4, 6
  • Côté, Jacques3
  • Sfeir, Agnel2
  • 1 Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
  • 2 Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 3 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. , (Canada)
  • 4 LifeB, Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic. , (Czechia)
  • 5 Skirball Institute of Biomolecular Medicine, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
  • 6 Institute of Biophysics of the Czech Academy of Sciences, Scientific Incubator, 612 65 Brno, Czech Republic. , (Cuba)
Type
Published Article
Journal
Genes & development
Publication Date
Mar 01, 2022
Volume
36
Issue
5-6
Pages
313–330
Identifiers
DOI: 10.1101/gad.349039.121
PMID: 35210222
Source
Medline
Keywords
Language
English
License
Unknown

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. © 2022 Barry et al.; Published by Cold Spring Harbor Laboratory Press.

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