The Daxx/Atrx Complex Protects Tandem Repetitive Elements during DNA Hypomethylation by Promoting H3K9 Trimethylation
Authors: Hyeung Kim
Fengtao Shi
Xiya Zhang
Junjiu Huang
Mengfan Tang
Quanyuan He
Zhou Songyang
Weisi Lu
Dong Yang
Rui Huang
Dan Liu
Journal: Cell Stem Cell (2015)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: ATRX; DAXX; DNA methylation; DNMTs; histone modification
Affiliations: 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., Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA., 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 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., 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: .

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. 

Retracted: No

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 There is a substantial issue concerning the validity of Daxx and ATRX KO lines generated in this paper. 1. Authors claim to have used sgRNA targeting first exon of Daxx and Atrx with Daxxsg1 GGCCACACAGTGCGACCCGG, Daxxsg2 CTCCTCCGGGTCGCACTGTG and Atrxsg1 AAAAGCAAATCAGAAACGCG. None of these sequences is actually matching the first exons of those genes. Both Daxx sgRNA sequences match the DNA sequence coding for aa724 to aa732 in the last exon, knowing that DAXX is 740aa long. Atrx sgRNA actually targets the first intron, about 1kb downstream of the first exon. Targeting the last exon or intron is an unusual strategy for efficient KO. 2. Since both Daxx antibodies were specifically designed against the C-terminus of the protein (aa627-739), which corresponds exactly to the targeted region by their crispr strategy (cf. above). It is therefore impossible to evaluate the validity of Daxx KO lines. It is quite possible that a version of DAXX truncated by a few amino acids is still expressed in those cell lines. https: www.scbt.com p daxx-antibody-m-112 https: www.scbt.com p daxx-antibody-c-20 ,