Daxx maintains endogenous retroviral silencing and restricts cellular plasticity in vivo

Sun, Chang; Moyer, Sydney M.; Qi, Yuan; Chau, Gilda; Aryal, Neeraj K.; McAllister, Florencia; Kim, Michael P.; Barton, Michelle C.; Estrella, Jeannelyn S.; Su, Xiaoping; Lozano, Guillermina

doi:10.1126/sciadv.aba8415

Cited by 26 publications

(48 citation statements)

References 61 publications

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“…Considering other H3.3 deposition pathways, conditional deletion of DAXX in pancreatic tissues supports its role in ERV silencing (Figure 2B and Table 1; Wasylishen et al, 2020). While no phenotypes were observed, the more permissible transcriptional state is proposed to increase responses to stressors and to impair recovery.…”

Section: Lineage Specific Differentiation a MIX Of In Vivo And Culture Systemsmentioning

confidence: 69%

Cell Fate Decisions in the Wake of Histone H3 Deposition

Franklin

Murn

Cheloufi

2021

Front. Cell Dev. Biol.

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An expanding repertoire of histone variants and specialized histone chaperone partners showcases the versatility of nucleosome assembly during different cellular processes. Recent research has suggested an integral role of nucleosome assembly pathways in both maintaining cell identity and influencing cell fate decisions during development and normal homeostasis. Mutations and altered expression profiles of histones and corresponding histone chaperone partners are associated with developmental defects and cancer. Here, we discuss the spatiotemporal deposition mechanisms of the Histone H3 variants and their influence on mammalian cell fate during development. We focus on H3 given its profound effect on nucleosome stability and its recently characterized deposition pathways. We propose that differences in deposition of H3 variants are largely dependent on the phase of the cell cycle and cellular potency but are also affected by cellular stress and changes in cell fate. We also discuss the utility of modern technologies in dissecting the spatiotemporal control of H3 variant deposition, and how this could shed light on the mechanisms of cell identity maintenance and lineage commitment. The current knowledge and future studies will help us better understand how organisms employ nucleosome dynamics in health, disease, and aging. Ultimately, these pathways can be manipulated to induce cell fate change in a therapeutic setting depending on the cellular context.

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Section: Lineage Specific Differentiation a MIX Of In Vivo And Culture Systemsmentioning

confidence: 69%

Cell Fate Decisions in the Wake of Histone H3 Deposition

Franklin

Murn

Cheloufi

2021

Front. Cell Dev. Biol.

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“…More recently, the same group developed mice with conditional Pdx1-Cre driven Daxx inactivation in the pancreas to better evaluate its function in pNETs (Table 2) [148]. Daxx loss alone had no effect on pancreas development and function, which remained normal, and surprisingly did not cooperate with Men1 loss to enhance pNET pathogenesis.…”

Section: Reference Key Findingsmentioning

confidence: 99%

Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Maharjan

Ear

Tran

et al. 2021

Cancers

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Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

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“…Recently [ 23 ], Wasylyshen et al explored, in mouse models, the role of DAXX and ATRX , the H3.3 histone variant chaperones, whose mutually exclusive mutations are found in about 43% of PanNETs [ 28 ]. The proteins encoded by DAXX and ATRX collaborate to form a heterodimeric complex that deposits the H3.3 histone variant into repetitive heterochromatin, including telomeres and retrotransposons [ 71 ].…”

Section: Permissive Chromatin Landscapementioning

confidence: 99%

Insights into Mechanisms of Tumorigenesis in Neuroendocrine Neoplasms

Pastorino

Grillo

Albertelli

et al. 2021

IJMS

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Genomic studies have identified some of the most relevant genetic players in Neuroendocrine Neoplasm (NEN) tumorigenesis. However, we are still far from being able to draw a model that encompasses their heterogeneity, elucidates the different biological effects consequent to the identified molecular events, or incorporates extensive knowledge of molecular biomarkers and therapeutic targets. Here, we reviewed recent insights in NEN tumorigenesis from selected basic research studies on animal models, highlighting novel players in the intergenic cooperation and peculiar mechanisms including splicing dysregulation, chromatin stability, or cell dedifferentiation. Furthermore, models of tumorigenesis based on composite interactions other than a linear progression of events are proposed, exemplified by the involvement in NEN tumorigenesis of genes regulating complex functions, such as MEN1 or DAXX. Although limited by interspecies differences, animal models have proved helpful for the more in-depth study of every facet of tumorigenesis, showing that the identification of driver mutations is only one of the many necessary steps and that other mechanisms are worth investigating.

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Daxx maintains endogenous retroviral silencing and restricts cellular plasticity in vivo

Cited by 26 publications

References 61 publications

Cell Fate Decisions in the Wake of Histone H3 Deposition

Cell Fate Decisions in the Wake of Histone H3 Deposition

Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Insights into Mechanisms of Tumorigenesis in Neuroendocrine Neoplasms

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