期刊
GENES & DEVELOPMENT
卷 36, 期 5-6, 页码 313-330出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.349039.121
关键词
RAP1; telomere; TIP60; EPC1; 2C-like; ZSCAN4; MERVL
资金
- National Institutes of Health (NIH) [R01 DK102562]
- Canadian Institutes of Health Research [FDN-143314]
- NIH [1F30 DK118901]
- Institute of Biophysics of the Czech Academy of Sciences [68081707]
- Czech Science Foundation [19-18226S]
- Ministry of Education, Youth, and Sports of the Czech Republic [LTAUSA19024]
- National Science and Engineering Council of Canada
- Fonds de Recherche du Quebec-Nature et Technologie
This study uncovers the mechanism of gene expression regulation by the telomere binding protein Rap1. Rap1 interacts with the TIP60/p400 complex and modulates its histone acetyltransferase activity. Deletion of Rap1 increases the fraction of two-cell-like cells in mouse embryonic stem cells and leads to upregulation of certain genes.
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 upregulation 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.
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