CTCF regulates the human p53 gene through direct interaction with its natural antisense transcript, Wrap53
- Ricardo Saldaña-Meyer1,2,
- Edgar González-Buendía1,
- Georgina Guerrero1,
- Varun Narendra2,
- Roberto Bonasio2,3,
- Félix Recillas-Targa1,4 and
- Danny Reinberg2,4
- 1Instituto de Fisiología Celular, Departamento de Genética Molecular, Universidad Nacional Autónoma de México, México City 04510, México;
- 2Howard Hughes Medical Institute, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
Abstract
The multifunctional CCCTC-binding factor (CTCF) protein exhibits a broad range of functions, including that of insulator and higher-order chromatin organizer. We found that CTCF comprises a previously unrecognized region that is necessary and sufficient to bind RNA (RNA-binding region [RBR]) and is distinct from its DNA-binding domain. Depletion of cellular CTCF led to a decrease in not only levels of p53 mRNA, as expected, but also those of Wrap53 RNA, an antisense transcript originated from the p53 locus. PAR-CLIP-seq (photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation [PAR-CLIP] combined with deep sequencing) analyses indicate that CTCF binds a multitude of transcripts genome-wide as well as to Wrap53 RNA. Apart from its established role at the p53 promoter, CTCF regulates p53 expression through its physical interaction with Wrap53 RNA. Cells harboring a CTCF mutant in its RBR exhibit a defective p53 response to DNA damage. Moreover, the RBR facilitates CTCF multimerization in an RNA-dependent manner, which may bear directly on its role in establishing higher-order chromatin structures in vivo.
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Footnotes
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↵4 Corresponding authors
E-mail danny.reinberg{at}nyumc.org
E-mail frecilla{at}correo.ifc.unam.mx
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.236869.113.
- Received December 20, 2013.
- Accepted February 26, 2014.
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