The Daxx/Atrx Complex Protects Tandem Repetitive Elements during DNA Hypomethylation by Promoting H3K9 Trimethylation.
The Daxx/Atrx Complex Protects Tandem Repetitive Elements during DNA Hypomethylation by Promoting H3K9 Trimethylation.
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Daxx/Atrx 复合物通过促进 H3K9 三甲基化在 DNA 低甲基化过程中保护串联重复元件
DOI：
10.1016/j.stem.2015.07.022
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发表时间：
2015-09-03
期刊：
影响因子：
23.9
通讯作者：
Songyang Z
中科院分区：
文献类型：
--
作者：
He Q;Kim H;Huang R;Lu W;Tang M;Shi F;Yang D;Zhang X;Huang J;Liu D;Songyang Z
在哺乳动物中，DNA甲基化是保护重复序列免受异常转录和重组的关键。在某些发育环境中(例如，植入前胚胎)，DNA的甲基化程度较低，但重复元件的调节并不失调，这表明存在替代的保护机制。在这里，我们通过研究染色质因子DAXX和ATRX的作用来探索涉及的过程。利用全基因组结合和转录组分析，我们发现DAXX和ATRX在野生型小鼠ESCs中具有不同的染色质结合谱，并在串联重复元件处共富集。全球DNA低甲基化进一步促进了DAXX/ATRX复合体向串联重复序列的招募，包括反转录转座子和端粒。在具有低甲基化基因组的细胞中，DAXX/ATRX的敲除加剧了重复元件的异常转录抑制和端粒功能障碍。从机制上讲，DAXX/ATRX介导的抑制似乎涉及SUV39H募集和H3K9三甲基化。因此，我们的数据表明，DAXX和ATRX通过在DNA甲基化水平较低时沉默重复元件来保护基因组。
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 wildtype 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.