Rap1 regulates TIP60 function during fate transition between two-cell-like and pluripotent states
© 2022 Barry et al.; Published by Cold Spring Harbor Laboratory Press..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:36 |
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| Enthalten in: |
Genes & development - 36(2022), 5-6 vom: 01. März, Seite 313-330 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Barry, Raymond Mario [VerfasserIn] |
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| Links: |
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| Themen: |
2C-like |
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| Anmerkungen: |
Date Completed 21.04.2022 Date Revised 02.09.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1101/gad.349039.121 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM337417717 |
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| 520 | |a © 2022 Barry et al.; Published by Cold Spring Harbor Laboratory Press. | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Stojaspal, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Kartsonis, William |e verfasserin |4 aut | |
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| 700 | 1 | |a Hofr, Ctirad |e verfasserin |4 aut | |
| 700 | 1 | |a Côté, Jacques |e verfasserin |4 aut | |
| 700 | 1 | |a Sfeir, Agnel |e verfasserin |4 aut | |
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