4.7 Article

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

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

  1. National Institutes of Health (NIH) [R01 DK102562]
  2. Canadian Institutes of Health Research [FDN-143314]
  3. NIH [1F30 DK118901]
  4. Institute of Biophysics of the Czech Academy of Sciences [68081707]
  5. Czech Science Foundation [19-18226S]
  6. Ministry of Education, Youth, and Sports of the Czech Republic [LTAUSA19024]
  7. National Science and Engineering Council of Canada
  8. Fonds de Recherche du Quebec-Nature et Technologie

向作者/读者索取更多资源

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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