Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells

Yuta Takahashi, Jun Wu, Keiichiro Suzuki, Paloma Martinez-Redondo, Mo Li, Hsin Kai Liao, Min Zu Wu, Reyna Hernández-Benítez, Tomoaki Hishida, Maxim Nikolaievich Shokhirev, Concepcion Rodriguez Esteban, Ignacio Sancho-Martinez, Juan Carlos Izpisua Belmonte

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

CpG islands (CGIs) are primarily promoter-associated genomic regions and are mostly unmethylated within highly methylated mammalian genomes. The mechanisms by which CGIs are protected from de novo methylation remain elusive. Here we show that insertion of CpG-free DNA into targeted CGIs induces de novo methylation of the entire CGI in human pluripotent stem cells (PSCs). The methylation status is stably maintained even after CpG-free DNA removal, extensive passaging, and differentiation. By targeting the DNA mismatch repair gene MLH1 CGI, we could generate a PSC model of a cancer-related epimutation. Furthermore, we successfully corrected aberrant imprinting in induced PSCs derived from an Angelman syndrome patient. Our results provide insights into how CpG-free DNA induces de novo CGI methylation and broaden the application of targeted epigenome editing for a better understanding of human development and disease.

Original languageEnglish (US)
Pages (from-to)503-508
Number of pages6
JournalScience
Volume356
Issue number6337
DOIs
StatePublished - May 5 2017
Externally publishedYes

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Pluripotent Stem Cells
CpG Islands
Methylation
DNA
Angelman Syndrome
Induced Pluripotent Stem Cells
DNA Mismatch Repair
Human Development
Genome
Genes
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Takahashi, Y., Wu, J., Suzuki, K., Martinez-Redondo, P., Li, M., Liao, H. K., ... Izpisua Belmonte, J. C. (2017). Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells. Science, 356(6337), 503-508. https://doi.org/10.1126/science.aag3260

Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells. / Takahashi, Yuta; Wu, Jun; Suzuki, Keiichiro; Martinez-Redondo, Paloma; Li, Mo; Liao, Hsin Kai; Wu, Min Zu; Hernández-Benítez, Reyna; Hishida, Tomoaki; Shokhirev, Maxim Nikolaievich; Rodriguez Esteban, Concepcion; Sancho-Martinez, Ignacio; Izpisua Belmonte, Juan Carlos.

In: Science, Vol. 356, No. 6337, 05.05.2017, p. 503-508.

Research output: Contribution to journalArticle

Takahashi, Y, Wu, J, Suzuki, K, Martinez-Redondo, P, Li, M, Liao, HK, Wu, MZ, Hernández-Benítez, R, Hishida, T, Shokhirev, MN, Rodriguez Esteban, C, Sancho-Martinez, I & Izpisua Belmonte, JC 2017, 'Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells', Science, vol. 356, no. 6337, pp. 503-508. https://doi.org/10.1126/science.aag3260
Takahashi, Yuta ; Wu, Jun ; Suzuki, Keiichiro ; Martinez-Redondo, Paloma ; Li, Mo ; Liao, Hsin Kai ; Wu, Min Zu ; Hernández-Benítez, Reyna ; Hishida, Tomoaki ; Shokhirev, Maxim Nikolaievich ; Rodriguez Esteban, Concepcion ; Sancho-Martinez, Ignacio ; Izpisua Belmonte, Juan Carlos. / Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells. In: Science. 2017 ; Vol. 356, No. 6337. pp. 503-508.
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