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

被引：55

作者：

Takahashi, Yuta ^{[1
,2
]}

Wu, Jun ^{[1
,3
]}

Suzuki, Keiichiro ^{[1
]}

Martinez-Redondo, Paloma

Li, Mo ^{[1
,4
]}

Liao, Hsin-Kai ^{[1
]}

Wu, Min-Zu ^{[1
,3
]}

Hernandez-Benitez, Reyna ^{[1
,4
]}

Hishida, Tomoaki ^{[1
]}

Shokhirev, Maxim Nikolaievich ^{[5
]}

Esteban, Concepcion Rodriguez ^{[1
]}

Sancho-Martinez, Ignacio ^{[1
,6
]}

Belmonte, Juan Carlos Izpisua ^{[1
]}

机构：

[1] Salk Inst Biol Studies, Gene Express Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA

[2] Univ Tsukuba, Tsukuba Adv Res Alliance, Life Sci Ctr, 1-1-1 Tennoudai, Tsukuba, Ibaraki 3058577, Japan

[3] Univ Catolica San Antonio Murcia UCAM, Campus Jeronimos 135, Murcia 30107, Spain

[4] King Abdullah Univ Sci & Technol, Thuwal 239556900, Saudi Arabia

[5] Salk Inst Biol Studies, Integrat Genom & Bioinformat Core, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA

[6] Novartis Fdn GNF, Genom Inst, Dept Pharmacol C128, 10675 John Jay Hopkins Dr, La Jolla, CA 92121 USA

来源：

SCIENCE | 2017年 / 356卷 / 6337期

关键词：

ANGELMAN-SYNDROME; COLORECTAL-CANCER; UBIQUITIN LIGASE; UBE3A; DIFFERENTIATION; SPECIFICATION; TRANSCRIPT; CONVERSION; PROMOTERS; MUTATION;

D O I：

10.1126/science.aag3260

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：503 / +

页数：6