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Rap1 regulates TIP60 function during fate transition between two-cell-like and pluripotent states
RM. Barry, O. Sacco, A. Mameri, M. Stojaspal, W. Kartsonis, P. Shah, P. De Ioannes, C. Hofr, J. Côté, A. Sfeir
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
F30 DK118901
NIDDK NIH HHS - United States
P30 CA008748
NCI NIH HHS - United States
R01 DK102562
NIDDK NIH HHS - United States
NLK
Free Medical Journals
from 1987 to 6 months ago
Freely Accessible Science Journals
from 1987-03-01 to 6 months ago
PubMed Central
from 1997 to 6 months ago
Europe PubMed Central
from 1997 to 6 months ago
Open Access Digital Library
from 1987-03-01
Open Access Digital Library
from 1987-01-01
- MeSH
- Genome MeSH
- Mouse Embryonic Stem Cells metabolism MeSH
- Mice MeSH
- Telomere-Binding Proteins * genetics metabolism MeSH
- Gene Expression Regulation MeSH
- Mammals genetics MeSH
- Telomere * metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
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.
References provided by Crossref.org
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