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 language | English (US) |
|---|---|
| Pages (from-to) | 503-508 |
| Number of pages | 6 |
| Journal | Science |
| Volume | 356 |
| Issue number | 6337 |
| DOIs | |
| State | Published - May 5 2017 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- General
Cite this
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 journal › Article
}
TY - JOUR
T1 - Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells
AU - Takahashi, Yuta
AU - Wu, Jun
AU - Suzuki, Keiichiro
AU - Martinez-Redondo, Paloma
AU - Li, Mo
AU - Liao, Hsin Kai
AU - Wu, Min Zu
AU - Hernández-Benítez, Reyna
AU - Hishida, Tomoaki
AU - Shokhirev, Maxim Nikolaievich
AU - Rodriguez Esteban, Concepcion
AU - Sancho-Martinez, Ignacio
AU - Izpisua Belmonte, Juan Carlos
PY - 2017/5/5
Y1 - 2017/5/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85018771317&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018771317&partnerID=8YFLogxK
U2 - 10.1126/science.aag3260
DO - 10.1126/science.aag3260
M3 - Article
C2 - 28473583
AN - SCOPUS:85018771317
VL - 356
SP - 503
EP - 508
JO - Science
JF - Science
SN - 0036-8075
IS - 6337
ER -