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Cell Stem Cell. 2015 Sep 3;17(3):273-86. doi: 10.1016/j.stem.2015.07.022.

The Daxx/Atrx Complex Protects Tandem Repetitive Elements during DNA Hypomethylation by Promoting H3K9 Trimethylation.

Author information

1
Key Laboratory of Gene Engineering of the Ministry of Education, SYSU-BCM Joint Center for Biomedical Sciences and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
2
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
3
Key Laboratory of Gene Engineering of the Ministry of Education, SYSU-BCM Joint Center for Biomedical Sciences and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
4
Key Laboratory of Gene Engineering of the Ministry of Education, SYSU-BCM Joint Center for Biomedical Sciences and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China; Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510275, China.
5
Key Laboratory of Gene Engineering of the Ministry of Education, SYSU-BCM Joint Center for Biomedical Sciences and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510275, China. Electronic address: songyang@bcm.edu.

Abstract

In mammals, DNA methylation is essential for protecting repetitive sequences from aberrant transcription and recombination. In some developmental contexts (e.g., preimplantation embryos) DNA is hypomethylated but repetitive elements are not dysregulated, suggesting that alternative protection mechanisms exist. Here we explore the processes involved by investigating the role of the chromatin factors Daxx and Atrx. Using genome-wide binding and transcriptome analysis, we found that Daxx and Atrx have distinct chromatin-binding profiles and are co-enriched at tandem repetitive elements in wild-type mouse ESCs. Global DNA hypomethylation further promoted recruitment of the Daxx/Atrx complex to tandem repeat sequences, including retrotransposons and telomeres. Knockdown of Daxx/Atrx in cells with hypomethylated genomes exacerbated aberrant transcriptional de-repression of repeat elements and telomere dysfunction. Mechanistically, Daxx/Atrx-mediated repression seems to involve Suv39h recruitment and H3K9 trimethylation. Our data therefore suggest that Daxx and Atrx safeguard the genome by silencing repetitive elements when DNA methylation levels are low.

KEYWORDS:

ATRX; DAXX; DNA methylation; DNMTs; histone modification; mouse embryonic stem cells; repetitive sequences; telomeres

Comment in

PMID:
26340527
PMCID:
PMC4571182
DOI:
10.1016/j.stem.2015.07.022
[Indexed for MEDLINE]
Free PMC Article

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