PML bodies provide an important platform for the maintenance of telomeric chromatin integrity in embryonic stem cells

Chang, Fiona T. M.; McGhie, James Derrick Robert; Chan, F. Lyn; Tang, Michelle C. W.; Anderson, Melissa A.; Mann, Jeffrey R.; Choo, K. H. Andy; Wong, Lee H.

doi:10.1093/nar/gkt114

Cited by 60 publications

(75 citation statements)

References 55 publications

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“…Previous studies have indicated that recruitment of histone chaperones and histones to PML bodies is indicative of trafficking of newly synthesized histones into chromatin (Chang et al 2013;Delbarre et al 2013;Corpet et al 2014). Consistent with ongoing histone deposition and nucleosome assembly in nonproliferating senescent cells, histone H3 was enriched in PML bodies of RS and OIS cells, where it colocalized with DNA replication-independent histone chaperone HIRA ( Fig.…”

Section: Resultssupporting

confidence: 67%

“…Second, in senescent cells, histones are enriched in PML bodies. This has been previously shown to reflect trafficking of newly synthesized histones into chromatin (Chang et al 2013;Delbarre et al 2013;Corpet et al 2014). Third, newly synthesized ectopically expressed and endogenous histones are actively incorporated into chromatin in senescent cells.…”

Section: Discussionmentioning

confidence: 85%

“…Here, we directly demonstrate that multiple features of the dynamic landscape in senescent cells are controlled by HIRA. HIRA colocalizes with histones in PML bodies of senescent cells, a presumptive marker of HIRA-mediated trafficking of histones into chromatin (Chang et al 2013;Delbarre et al 2013). HIRA is required for the accumulation of histones in PML bodies and also for the deposition and/or accumulation of newly synthesized H3 (presumably H3.3) and H4 into chromatin of senescent cells.…”

Section: Discussionmentioning

confidence: 99%

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HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia

et al. 2014

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Cellular senescence is a stable proliferation arrest that suppresses tumorigenesis. Cellular senescence and associated tumor suppression depend on control of chromatin. Histone chaperone HIRA deposits variant histone H3.3 and histone H4 into chromatin in a DNA replication-independent manner. Appropriately for a DNA replication-independent chaperone, HIRA is involved in control of chromatin in nonproliferating senescent cells, although its role is poorly defined. Here, we show that nonproliferating senescent cells express and incorporate histone H3.3 and other canonical core histones into a dynamic chromatin landscape. Expression of canonical histones is linked to alternative mRNA splicing to eliminate signals that confer mRNA instability in nonproliferating cells. Deposition of newly synthesized histones H3.3 and H4 into chromatin of senescent cells depends on HIRA. HIRA and newly deposited H3.3 colocalize at promoters of expressed genes, partially redistributing between proliferating and senescent cells to parallel changes in expression. In senescent cells, but not proliferating cells, promoters of active genes are exceptionally enriched in H4K16ac, and HIRA is required for retention of H4K16ac. HIRA is also required for retention of H4K16ac in vivo and suppression of oncogeneinduced neoplasia. These results show that HIRA controls a specialized, dynamic H4K16ac-decorated chromatin landscape in senescent cells and enforces tumor suppression.

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Section: Resultssupporting

confidence: 67%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia

et al. 2014

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“…The basis for these discrepancies is not clear but might be related to the strain of virus or to the fundamental differences in the composition of PML bodies. Indeed, in contrast to many other cell types, hDaxx and ATRX foci are mostly excluded from PML bodies in ES cells, pNSCs, and NPCs during G 1 and are instead located at heterochromatin loci (33,34; data not shown). Nevertheless, given the fundamental role of hDaxx in the maintenance of pluripotency and multipotency in ES and neural stem cells, respectively (35,36), our results suggest that HCMV might impact cell function even in the absence of productive infection of the targeted cells.…”

Section: Discussionmentioning

confidence: 84%

Human Cytomegalovirus Infection of Human Embryonic Stem Cell-Derived Primitive Neural Stem Cells Is Restricted at Several Steps but Leads to the Persistence of Viral DNA

Belzile

Stark

Yeo

et al. 2014

J Virol

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Congenital human cytomegalovirus (HCMV) infection is a major cause of central nervous system structural anomalies and sensory impairments. It is likely that the stage of fetal development, as well as the state of differentiation of susceptible cells at the time of infection, affects the severity of the disease. We used human embryonic stem (ES) cell-derived primitive prerosette neural stem cells (pNSCs) and neural progenitor cells (NPCs) maintained in chemically defined conditions to study HCMV replication in cells at the early stages of neural development. In contrast to what was observed previously using fetus-derived NPCs, infection of ES cell-derived pNSCs with HCMV was nonprogressive. At a low multiplicity of infection, we observed only a small percentage of cells expressing immediate-early genes (IE) and early genes. IE expression was found to be restricted to cells negative for the anterior marker FORSE-1, and treatment of pNSCs with retinoic acid restored IE expression. Differentiation of pNSCs into NPCs restored IE expression but not the transactivation of early genes. Virions produced in NPCs and pNSCs were exclusively cell associated and were mostly non-neural tropic. Finally, we found that viral genomes could persist in pNSC cultures for up to a month after infection despite the absence of detectable IE expression by immunofluorescence, and infectious virus could be produced upon differentiation of pNSCs to neurons. In conclusion, our results highlight the complex array of hurdles that HCMV must overcome in order to infect primitive neural stem cells and suggest that these cells might act as a reservoir for the virus. IMPORTANCEHuman cytomegalovirus (HCMV) is a betaherpesvirus that is highly prevalent in the population. HCMV infection is usually asymptomatic but can lead to severe consequences in immunosuppressed individuals. HCMV is also the most important infectious cause of congenital developmental birth defects. Manifestations of fetal HCMV disease range from deafness and learning disabilities to more severe symptoms such as microcephaly. In this study, we have used embryonic stem cells to generate primitive neural stem cells and have used these to model HCMV infection of the fetal central nervous system (CNS) in vitro. Our results reveal that these cells, which are similar to those present in the developing neural tube, do not support viral replication but instead likely constitute a viral reservoir. Future work will define the effect of viral persistence on cellular functions as well as the exogenous signals leading to the reactivation of viral replication in the CNS. Human cytomegalovirus (HCMV) is the most important infectious cause of congenital developmental birth defects, with the central nervous system (CNS) being a main target. The incidence of fetal transmission is between 1 and 4% of live births. At birth, 5 to 10% of in utero-infected infants display symptoms of CMV inclusion disease, which can range from mild to severe and is often lethal. Neural developmental abnormalities i...

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“…More recently, Atrxnull mouse embryonic brain cells were shown to exhibit telomeric damage that could be worsened by treatment with the G-quadruplex ligand telomestatin, suggesting a role for ATRX in the replication of telomeric G4-DNA structures (39). In mouse embryonic stem cells, ATRX and H3.3 colocalized within PML bodies containing telomeric DNA (40). Interestingly, such PML bodies likely correspond to the APBs found in ALT-positive cancer cells (9,19).…”

Section: Discussionmentioning

confidence: 99%

Genetic Inactivation of ATRX Leads to a Decrease in the Amount of Telomeric Cohesin and Level of Telomere Transcription in Human Glioma Cells

Eid

Demattei

Episkopou

et al. 2015

Molecular and Cellular Biology

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cMutations in ATRX (alpha thalassemia/mental retardation syndrome X-linked), a chromatin-remodeling protein, are associated with the telomerase-independent ALT (alternative lengthening of telomeres) pathway of telomere maintenance in several types of cancer, including human gliomas. In telomerase-positive glioma cells, we found by immunofluorescence that ATRX localized not far from the chromosome ends but not exactly at the telomere termini. Chromatin immunoprecipitation (ChIP) experiments confirmed a subtelomeric localization for ATRX, yet short hairpin RNA (shRNA)-mediated genetic inactivation of ATRX failed to trigger the ALT pathway. Cohesin has been recently shown to be part of telomeric chromatin. Here, using ChIP, we showed that genetic inactivation of ATRX provoked diminution in the amount of cohesin in subtelomeric regions of telomerasepositive glioma cells. Inactivation of ATRX also led to diminution in the amount of TERRAs, noncoding RNAs resulting from transcription of telomeric DNA, as well as to a decrease in RNA polymerase II (RNAP II) levels at the telomeres. Our data suggest that ATRX might establish functional interactions with cohesin on telomeric chromatin in order to control TERRA levels and that one or the other or both of these events might be relevant to the triggering of the ALT pathway in cancer cells that exhibit genetic inactivation of ATRX.T he linear chromosomes of eukaryotic organisms require particular protection at their extremities. Telomeres, which represent the ends of these chromosomes and contain repeated TGrich sequences that do not code for proteins, as well as proteins of the shelterin complex, are essential for this protection (1). Telomeres protect chromosome ends from DNA repair activities that reseal chromosome internal DNA breaks occurring during DNA damage (2). Telomere sequences naturally erode with ongoing cell divisions, due to intrinsic mechanisms associated with the fixed 5=-to-3= polarity of replication of the DNA of the genome. Below a certain threshold, shortened telomeres result in DNA damageinduced cell cycle arrest, which is the equivalent of replicative senescence in cultured cells.By limiting the replicative potential of cells, telomere length acts as a biological clock, and telomere erosion serves as a barrier against tumorigenesis in healthy tissue. Paradoxically, telomere erosion or telomere dysfunction also induces chromosomal instability and favors the emergence of tumors (3). However, following cancer initiation, tumor cells must overcome the telomere-controlled replicative-senescence barrier, and all have an absolute necessity to maintain functional telomeres in order to sustain continuous and unlimited cell proliferation. In around 85 to 90% of cancer types, this occurs through upregulation of telomerase, a reverse transcriptase with a built-in RNA template specialized in telomeric DNA replication that is naturally repressed in most somatic tissues (4). In the remaining 10 to 15% of cancer types, an alternative pathway called the ALT (alternativ...

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PML bodies provide an important platform for the maintenance of telomeric chromatin integrity in embryonic stem cells

Cited by 60 publications

References 55 publications

HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia

HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia

Human Cytomegalovirus Infection of Human Embryonic Stem Cell-Derived Primitive Neural Stem Cells Is Restricted at Several Steps but Leads to the Persistence of Viral DNA

Genetic Inactivation of ATRX Leads to a Decrease in the Amount of Telomeric Cohesin and Level of Telomere Transcription in Human Glioma Cells

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