Dataset Information

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

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.

SUBMITTER: He Q

PROVIDER: S-EPMC4571182 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

He Quanyuan Q Kim Hyeung H Huang Rui R Lu Weisi W Tang Mengfan M Shi Fengtao F Yang Dong D Zhang Xiya X Huang Junjiu J Liu Dan D Songyang Zhou Z

Cell stem cell 20150901 3

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 h ...[more]

PMID: 26340527

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Project description:In mammals, DNA methylation is essential for protecting repetitive sequences from aberrant transcription, translocation, and homologous recombination. However, DNA hypomethylation occurs during specific developmental stages (e.g. preimplantation embryos) and in certain cell types (e.g., primordial germ cells). The absence of dysregulated repetitive elements in these cells suggests the existence of alternative mechanisms that prevent genome instability triggered by DNA hypomethylation. In this report, we seek to elucidate the factors that play a critical role in ensuring genome stability by focusing on DAXX and ATRX, two proteins that have been linked to transcriptional control and epigenetic regulation. We carried out ChIP-seq and RNA-seq analyses to compare the genome-wide binding and transcriptome profiles of DAXX and ATRX in mouse ES (mES) cells triple knocked out for the three mammalian DNA methyltransferases (DNMTs) (TKO cells) to those in wildtype mES cells. Our data indicate that DAXX and ATRX are distinct in their chromatin-binding profiles and highly co-enriched at tandem repetitive elements. Global DNA hypomethylation, as was the case in TKO cells, further promoted the recruitment of the DAXX/ATRX complex to tandem repeat sequences including IAP (intracisternal A‐particle) retrotransposons and telomeres. Inhibition of DAXX or ATRX in cells with hypomethylated genomes (e.g., TKO cells, mES cells cultured in ground-state conditions, and preimplantation embryos) increased aberrant transcriptional de-repression of repeat elements and dysfunction at telomeres. Furthermore, we provide evidence that DAXX/ATRX-dependent silencing may occur through DAXX’s interaction with SUV39H1 and increased H3K9me3 on repetitive sequences. Our study suggests that DAXX and ATRX are important for safeguarding the genome, particularly in silencing repetitive elements in the absence of DNA methylation. We tested the hypothesis that the DAXX/ATRX complex participates in protecting repetitive elements in the absence of DNA methylation. To this end, we investigated genome-wide chromatin targeting of DAXX and ATRX in wildtype mES cells, and in mES cells that exhibit extensive loss of DNA methylation due to homozygous knockout of all three DNA.

Project description:Telomeres are nucleoprotein complexes located at the termini of eukaryotic chromosomes that prevent exonucleolytic degradation and end-to-end chromosomal fusions. Cancers often have critically shortened, dysfunctional telomeres contributing to genomic instability. Telomere shortening has been reported in a wide range of precancerous lesions and invasive carcinomas. However, the role of telomere alterations, including the presence of alternative lengthening of telomeres (ALT), has not been studied in pituitary adenomas. Telomere length and the presence of ALT were assessed directly at the single cell level using a telomere-specific fluorescence in situ hybridization assay in tissue microarrays. Tumors were characterized as either ALT-positive or having short, normal, or long telomere lengths and then these categories were compared with clinicopathological characteristics. ATRX and DAXX expression was studied through immunohistochemistry. We characterized a discovery set of 106 pituitary adenomas including both functional and nonfunctional subsets (88 primary, 18 recurrent). Telomere lengths were estimated and we observed 64 (59.4%) cases with short, 39 (36.8%) cases with normal, and 0 (0%) cases with long telomeres. We did not observe significant differences in the clinicopathological characteristics of the group with abnormally shortened telomeres compared to the group with normal telomeres. However, three pituitary adenomas were identified as ALT-positive of which two were recurrent tumors. Two of these three ALT-positive cases had alterations in either of the chromatin remodeling proteins, ATRX and DAXX, which are routinely altered in other ALT-positive tumor subtypes. In a second cohort of 32 recurrent pituitary adenomas from 22 patients, we found that the tumors from 36% of patients (n = 8) were ALT-positive. This study demonstrates that short telomere lengths are prevalent in pituitary adenomas and that ALT-positive pituitary adenomas are enriched in recurrent disease.

Dataset Information

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

Publications

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

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