Rap1 regulates TIP60 function during fate transition between two-cell-like and pluripotent states
- Raymond Mario Barry1,2,
- Olivia Sacco2,
- Amel Mameri3,
- Martin Stojaspal1,4,
- William Kartsonis1,
- Pooja Shah1,
- Pablo De Ioannes5,
- Ctirad Hofr4,6,
- Jacques Côté3 and
- Agnel Sfeir2
- 1Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA;
- 2Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
- 3St-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;
- 4LifeB, Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic;
- 5Skirball Institute of Biomolecular Medicine, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA;
- 6Institute of Biophysics of the Czech Academy of Sciences, Scientific Incubator, 612 65 Brno, Czech Republic
- Corresponding author: sfeira{at}mskcc.org
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.
Keywords
Footnotes
-
Supplemental material is available for this article.
-
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.349039.121.
- Received October 7, 2021.
- Accepted February 8, 2022.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.