The loss of ATRX/DAXX complex disturbs rDNA heterochromatinization and promotes development of glioma

Cheng, Xiaohuan; Jiang, Qi; Hu, Xinyang; Huang, Xingwei; Liu, Hui; Wang, Yongmei; N, Li; Wang, N; Shen, Jingling; Zhang, Y; Le, Lei

doi:10.1101/745307

Cited by 3 publications

(3 citation statements)

References 69 publications

(90 reference statements)

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“…Only very recently it was observed that ATRX binds to several proteins directly involved in ribosome biogenesis 36 . Another report showed that ATRX binds to the promotor region of rDNA and that in gliomas with nonsense mutations increased ribosome biogenesis can be observed, which is in line with our generated ATRX KO models 37 . Intriguingly, for the majority of our created models we did not observe changed proliferative rates, however we observed several altered metabolic processes in our data.…”

Section: Discussionsupporting

confidence: 90%

Two opposing gene expression patterns withinATRXaberrant neuroblastoma

Gerven

Schild

Arkel

et al. 2022

Preprint

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Neuroblastoma is the most common extracranial solid tumor in children. A subgroup of high-risk patients is characterized by aberrations in the chromatin remodeller ATRX that is encoded by 35 exons. In contrast to other pediatric cancer where ATRX point mutations are most frequent, multi-exon deletions (MEDs) are the most frequent type of ATRX aberrations in neuroblastoma. Of these MEDs 75% are predicted to produce in-frame fusion proteins, suggesting a potential gain-of-function effect compared to nonsense mutations. For neuroblastoma there are only a few patient-derived ATRX aberrant models. Therefore, we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid and performed total RNA-sequencing on these and on the patient-derived model. Gene set enrichment analysis (GSEA) showed decreased expression of genes related to both ribosome biogenesis and several metabolic process in our isogenic ATRX exon 2-10 MED model systems, the patient-derived MED models and in tumor data containing two patients with an ATRX exon 2-10 MED. Interestingly, for our isogenic ATRX knock-out and exon 2-13 MED models GSEA revealed an opposite expression pattern characterized by increased expression of genes related to ribosome biogenesis and several metabolic process. Our validations confirmed a potential role of ATRX in the regulation of ribosome homeostasis. In this manner we identified two distinct molecular expression patterns within ATRX aberrant neuroblastomas with important implications for the need of distinct treatment regimens.

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Section: Discussionsupporting

confidence: 90%

Two opposing gene expression patterns withinATRXaberrant neuroblastoma

Gerven

Schild

Arkel

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Only very recently it was observed that ATRX binds to several proteins directly involved in ribosome biogenesis [37]. Another report showed that ATRX binds to the promotor region of rDNA and they observed increased ribosome biogenesis in gliomas with nonsense mutations, which is in line with our generated ATRX KO models [38]. This could suggest that increased ribosome biogenesis as a result of an ATRX nonsense mutation or KO, is a more general phenomenon in cancer.…”

Section: Plos Onesupporting

confidence: 86%

Two opposing gene expression patterns within ATRX aberrant neuroblastoma

et al. 2023

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Neuroblastoma is the most common extracranial solid tumor in children. A subgroup of high-risk patients is characterized by aberrations in the chromatin remodeller ATRX that is encoded by 35 exons. In contrast to other pediatric cancer where ATRX point mutations are most frequent, multi-exon deletions (MEDs) are the most frequent type of ATRX aberrations in neuroblastoma. 75% of these MEDs are predicted to produce in-frame fusion proteins, suggesting a potential gain-of-function effect compared to nonsense mutations. For neuroblastoma there are only a few patient-derived ATRX aberrant models. Therefore, we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid and performed total RNA-sequencing on these and the patient-derived models. Gene set enrichment analysis (GSEA) showed decreased expression of genes related to both ribosome biogenesis and several metabolic processes in our isogenic ATRX exon 2–10 MED model systems, the patient-derived MED models and in tumor data containing two patients with an ATRX exon 2–10 MED. In sharp contrast, these same processes showed an increased expression in our isogenic ATRX knock-out and exon 2–13 MED models. Our validations confirmed a role of ATRX in the regulation of ribosome homeostasis. The two distinct molecular expression patterns within ATRX aberrant neuroblastomas that we identified imply that there might be a need for distinct treatment regimens.

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“…DAXX/ATRX mediates H3.3 incorporation into the repetitive elements to silence them is important for maintaining genomic stability. Depletion of Daxx may reduce rDNA heterochromatinization, and our previous studies indicated that DAXX depletion leads to the conversion of silent rDNA into upstream binding factor‐bound active rDNA and the release of rDNA transcriptional potency (Cheng et al, 2019), and Daxx knockout promotes the expression of rDNA in mouse induced pluripotential stem cells (Liu, Liu, et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Daxx knockdown promoted rDNA transcription without impairing H3.3 expression in mouse preimplantation embryos

Song,

Wang,

Huang

et al. 2023

Anat Histol Embryol

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During fertilization, DAXX (death domain‐associated protein) mediates histone variant H3.3 incorporation into heterochromatin, which plays an important role in the maintenance of genomic integrity. rDNA, the ribosomal gene, is included in the first wave of gene activation after fertilization. Our and other studies indicated that loss of Daxx disturbs rDNA heterochromatinization and promotes rDNA transcription without change in protein expression of H3.3. However, maternal and zygotic deletion of Daxx impairs blastocyst development. Whether Daxx knockdown affects H3.3 expression and improves the rDNA transcription in preimplantation development has not been reported. In the present study, we injected HA‐labelled H3.3 (H3.3‐HA) into oocytes during ICSI procedure, and detected H3.3 and DAXX by immunofluorescent staining. Then, we knockdowned Daxx and detected the gene expression levels of Daxx, H3.3, 18s and 47s rRNA. We also performed immunofluorescent staining of B23, γH2A and EdU incorporation to demonstrate nuclear structure, DNA damage and replication. We found injection of H3.3‐HA did not impair preimplantation development. Daxx siRNA did not change expression of H3.3 mRNA, and the development of two‐cell embryos and blastocysts, but the overall replication and expression levels of rRNA were increased compared with that in the control group. Finally, knockdown of DAXX did not aggravate the DNA damage but loosened the nucleolus. We concluded that Daxx knockdown promoted DNA replication and rDNA transcription, but did not affect H3.3 expression and subsequent preimplantation development.

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The loss of ATRX/DAXX complex disturbs rDNA heterochromatinization and promotes development of glioma

Cited by 3 publications

References 69 publications

Two opposing gene expression patterns withinATRXaberrant neuroblastoma

Two opposing gene expression patterns withinATRXaberrant neuroblastoma

Two opposing gene expression patterns within ATRX aberrant neuroblastoma

Daxx knockdown promoted rDNA transcription without impairing H3.3 expression in mouse preimplantation embryos

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