The Daxx/Atrx Complex Protects Tandem Repetitive Elements during DNA Hypomethylation by Promoting H3K9 Trimethylation.
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.
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.
Quanyuan
Q
He
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Hyeung
H
Kim
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.
Rui
R
Huang
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.
Weisi
W
Lu
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.
Mengfan
M
Tang
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Fengtao
F
Shi
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Dong
D
Yang
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.
Xiya
X
Zhang
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.
Junjiu
J
Huang
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Dan
D
Liu
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.
Zhou
Z
Songyang
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000378:metabolism*; D019175:DNA Methylation; D047108:Embryonic Development; D016678:Genome; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D020080:Tandem Repeat Sequences / Q000235:genetics*; D016615:Telomere / Q000378:metabolism; D014158:Transcription, Genetic; D000075924:X-linked Nuclear Protein
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C491473:Daxx protein, mouse; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases; D004265:DNA Helicases; C092332:ATRX protein, human; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein; D008239:Lysine
ATRX; DAXX; DNA methylation; DNMTs; histone modification; mouse embryonic stem cells; repetitive sequences; telomeres