CTCF is a barrier for 2C-like reprogramming

Teresa Olbrich, Maria Vega-Sendino, Desiree Tillo, Wei Wu, Nicholas Zolnerowich, Raphael Pavani, Andy D. Tran, Catherine N. Domingo, Mariajose Franco, Marta Markiewicz-Potoczny, Gianluca Pegoraro, Peter C. FitzGerald, Michael J. Kruhlak, Eros Lazzerini-Denchi, Elphege P. Nora, André Nussenzweig and Sergio Ruiz ()
Additional contact information
Teresa Olbrich: Laboratory of Genome Integrity, CCR, NCI, NIH
Maria Vega-Sendino: Laboratory of Genome Integrity, CCR, NCI, NIH
Desiree Tillo: Genetics Branch, CCR, NCI, NIH
Wei Wu: Laboratory of Genome Integrity, CCR, NCI, NIH
Nicholas Zolnerowich: Laboratory of Genome Integrity, CCR, NCI, NIH
Raphael Pavani: Laboratory of Genome Integrity, CCR, NCI, NIH
Andy D. Tran: Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH
Catherine N. Domingo: Laboratory of Genome Integrity, CCR, NCI, NIH
Mariajose Franco: Laboratory of Genome Integrity, CCR, NCI, NIH
Marta Markiewicz-Potoczny: Laboratory of Genome Integrity, CCR, NCI, NIH
Gianluca Pegoraro: Laboratory of Receptor Biology and Gene Expression, CCR, NCI, NIH
Peter C. FitzGerald: Genome Analysis Unit, CCR, NCI, NIH
Michael J. Kruhlak: Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH
Eros Lazzerini-Denchi: Laboratory of Genome Integrity, CCR, NCI, NIH
Elphege P. Nora: University of California San Francisco
André Nussenzweig: Laboratory of Genome Integrity, CCR, NCI, NIH
Sergio Ruiz: Laboratory of Genome Integrity, CCR, NCI, NIH

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Totipotent cells have the ability to generate embryonic and extra-embryonic tissues. Interestingly, a rare population of cells with totipotent-like potential, known as 2 cell (2C)-like cells, has been identified within ESC cultures. They arise from ESC and display similar features to those found in the 2C embryo. However, the molecular determinants of 2C-like conversion have not been completely elucidated. Here, we show that the CCCTC-binding factor (CTCF) is a barrier for 2C-like reprogramming. Indeed, forced conversion to a 2C-like state by the transcription factor DUX is associated with DNA damage at a subset of CTCF binding sites. Depletion of CTCF in ESC efficiently promotes spontaneous and asynchronous conversion to a 2C-like state and is reversible upon restoration of CTCF levels. This phenotypic reprogramming is specific to pluripotent cells as neural progenitor cells do not show 2C-like conversion upon CTCF-depletion. Furthermore, we show that transcriptional activation of the ZSCAN4 cluster is necessary for successful 2C-like reprogramming. In summary, we reveal an unexpected relationship between CTCF and 2C-like reprogramming.

Date: 2021
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DOI: 10.1038/s41467-021-25072-x

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