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ABSTRACT:
PROVIDER: PRJEB27501 | ENA |
REPOSITORIES: ENA
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Project description:Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against herpes simplex virus 1 (HSV-1) infection. Following the activation of innate immune signalling, HIRA localized at PML-NBs in a Janus-Associated Kinase (JAK), Cyclin Dependent Kinase (CDK), and Sp100-dependent manner. RNA-seq analysis revealed that HIRA promoted the transcriptional upregulation of a broad repertoire of host genes that regulate innate immunity to HSV-1 infection, including those involved in MHC-I antigen presentation, cytokine signalling, and interferon stimulated gene (ISG) expression. ChIP-seq analysis revealed that PML, the principle scaffolding protein of PML-NBs, was required for the enrichment of HIRA onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immunity to virus infection. Our data identifies independent roles for HIRA in the intrinsic silencing of viral gene expression and the induction of innate immune defences to restrict the initiation and propagation of HSV-1 infection, respectively. These intracellular host defences are antagonized by the HSV-1 ubiquitin ligase ICP0, which disrupts the stable recruitment of HIRA to infecting viral genomes and PML-NBs at spatiotemporally distinct phases of infection. Our study highlights the importance of histone chaperones to regulate multiple phases of intracellular immunity to virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.
2019-03-12 | GSE128173 | GEO
Project description:Promyelocytic Leukemia Nuclear Bodies (PML NBs) are nuclear membrane-less organelles physically associated with chromatin underscoring their crucial role in genome function. The H3.3 histone chaperone complex HIRA accumulates in PML NBs upon senescence, viral infection or IFN-I treatment in primary cells. Yet, the molecular mechanisms of this partitioning and its function in regulating histone dynamics have remained elusive. Here, by using specific siRNAs and protein Affimers, we identify intermolecular SUMO-SIM interactions as an essential mechanism for HIRA recruitment in PML NBs. In addition, we demonstrate that HIRA localization in the nuclear bodies is intimately linked to the presence of a soluble pool of H3.3-H4 dimers inside PML NBs, that is not found in cancer cells. Transcription inhibition prevents HIRA accumulation in PML NBs underscoring the importance of transcriptional activity to drive HIRA through PML NBs. Finally, in the context of inflammatory responses, HIRA and PML are necessary for the prolonged H3.3 deposition at the transcriptional end sites of interferon-stimulated genes (ISGs), well beyond the peak of transcription. We thus propose that HIRA partitioning in PML NBs is essential to regulate H3.3 deposition on transcriptionally active regions.
2023-05-25 | GSE233298 | GEO
Project description:Promyelocytic Leukemia Nuclear Bodies (PML NBs) are nuclear membrane-less organelles physically associated with chromatin underscoring their crucial role in genome function. The H3.3 histone chaperone complex HIRA accumulates in PML NBs upon senescence, viral infection or IFN-I treatment in primary cells. Yet, the molecular mechanisms of this partitioning and its function in regulating histone dynamics have remained elusive. Here, by using specific siRNAs and protein Affimers, we identify intermolecular SUMO-SIM interactions as an essential mechanism for HIRA recruitment in PML NBs. In addition, we demonstrate that HIRA localization in the nuclear bodies is intimately linked to the presence of a soluble pool of H3.3-H4 dimers inside PML NBs, that is not found in cancer cells. Transcription inhibition prevents HIRA accumulation in PML NBs underscoring the importance of transcriptional activity to drive HIRA through PML NBs. Finally, in the context of inflammatory responses, HIRA and PML are necessary for the prolonged H3.3 deposition at the transcriptional end sites of interferon-stimulated genes (ISGs), well beyond the peak of transcription. We thus propose that HIRA partitioning in PML NBs is essential to regulate H3.3 deposition on transcriptionally active regions.
2023-05-30 | GSE186937 | GEO
Project description:The histone chaperone HIRA promotes the induction of host innate immune defences in response to HSV-1 infection
| PRJNA526670 | ENA
Project description:A previous study has shown that PML-dependent recruitment of HIRA to ISG promoters contributes to the up-regulation of gene expression as a result of cytokine release in response to HSV infection (McFarlane et al., 2019). Although carried out in non-neuronal cells, this study and others (Ulbricht et al., 2012, Kim and Ahn, 2015, Scherer et al., 2016, Chen et al., 2015) suggest that PML itself may contribute to ISG upregulation, so to determine whether PML was indeed required for ISG stimulation in SCG neurons, we carried out RNA sequence analysis in IFNα-treated neurons depleted of PML.
2021-06-21 | GSE166738 | GEO
Project description:TRIM33 is a chromatin reader required for mesendoderm differentiation upon activation of Nodal signaling. But, its role in mESCs is still elusive. Here, we found that TRIM33 co-localizes with promyelocytic leukemia nuclear bodies (PML NBs) specifically in mESCs to mediate Nodal signaling-directed transcription of Lefty1/2. We showed that TRIM33 puncta formation in mESCs depends on PML and specific assembly of PML NBs. Moreover, TRIM33 and PML co-regulate Lefty1/2 expression in mESCs. In addition, both PML and mESCs-specific PML NBs are required for TRIM33 recruitment at Lefty1/2 loci. Remarkably, PML NBs directly associate with the Lefty1/2 loci in mESCs. Finally, a TurboID proximity labeling experiment confirmed that TRIM33 is highly enriched in the mESCs-specific PML NBs. Thus, our study provides the mechanistic insight about TRIM33 condensate in regulating Nodal signaling-directed transcription in mESCs, it also reveals that PML NBs recruit distinct sets of client proteins in cell context dependent manner.
2022-12-08 | GSE199738 | GEO
Project description:TRIM33 is a chromatin reader required for nodal signaling during mesendoderm differentiation, although differences in its function between mouse embryonic stem cells (mESCs) and differentiated mesendoderm cells are unknown. Here, we found that TRIM33 co-condenses with PML nuclear bodies (NBs) via liquid-liquid phase separation specifically in mESCs to mediate nodal signaling-directed transcription of Lefty1/2. Our findings show that TRIM33 puncta formation depends on the presence of PML NBs. TurboID proximity labeling further revealed that PML NBs recruit distinct sets of client proteins in NaAsO2-treated, untreated mESCs, and differentiated cells. TRIM33 and PML co-regulate Lefty1/2 expression, while PML NBs directly associate with the Lefty1/2 loci and regulate a gene cluster that includes Lefty1/2 loci specifically in mESCs. Moreover, TRIM33 association with chromatin depends on PML NBs. Thus, PML NBs serve as a hub for transcriptional regulation of Lefty1/2 by TRIM33 and other pluripotency factors in mESCs.
2022-12-08 | GSE199737 | GEO
Project description:TRIM33 is a chromatin reader required for nodal signaling during mesendoderm differentiation, although differences in its function between mouse embryonic stem cells (mESCs) and differentiated mesendoderm cells are unknown. Here, we found that TRIM33 co-condenses with PML nuclear bodies (NBs) via liquid-liquid phase separation specifically in mESCs to mediate nodal signaling-directed transcription of Lefty1/2. Our findings show that TRIM33 puncta formation depends on the presence of PML NBs. TurboID proximity labeling further revealed that PML NBs recruit distinct sets of client proteins in NaAsO2-treated, untreated mESCs, and differentiated cells. TRIM33 and PML co-regulate Lefty1/2 expression, while PML NBs directly associate with the Lefty1/2 loci and regulate a gene cluster that includes Lefty1/2 loci specifically in mESCs. Moreover, TRIM33 association with chromatin depends on PML NBs. Thus, PML NBs serve as a hub for transcriptional regulation of Lefty1/2 by TRIM33 and other pluripotency factors in mESCs.
2022-12-08 | GSE199736 | GEO
Project description:Regular nuclear structure is critical for genome maintenance and proper gene expression, disorder of which has a causal role in aging. Accumulation of Progerin in Hutchinson-Gilford progeria syndrome (HGPS) disrupts the integrity of nuclear lamina and causes nuclear structure abnormalities, leading to premature aging. However, the nuclear structure/function relationships in HGPS cells have not been well addressed, and roles of nuclear sub-compartments for HGPS pathogenesis are rarely reported. Here, evidence reveals that classical dot-like PML nuclear bodies (PML NBs) are reorganized into thread-like morphology in HGPS cells, and these irregular NBs are strongly associated with cell senescence. We demonstrate that farnesylated Progerin interacts with PML isoform 2 specifically, which accounts for the formation of thread-like PML NBs. Moreover, our findings uncover that irregular PML NBs perturb NBs-associated DNA repair and gene transcription, thereby promoting HGPS cell senescence. Thus, our work helps to clarify the roles of nuclear structure and sub-compartments such as PML NBs in cell aging, and evidence presented in this study strongly support that thread-like PML NBs could be a novel biomarker of human cell senescence.
2019-09-10 | GSE137084 | GEO
Project description:Regular nuclear structure is critical for genome maintenance and proper gene expression, disorder of which has a causal role in aging. Accumulation of Progerin in Hutchinson-Gilford progeria syndrome (HGPS) disrupts the integrity of nuclear lamina and causes nuclear structure abnormalities, leading to premature aging. However, the nuclear structure/function relationships in HGPS cells have not been well addressed, and roles of nuclear sub-compartments for HGPS pathogenesis are rarely reported. Here, evidence reveals that classical dot-like PML nuclear bodies (PML NBs) are reorganized into thread-like morphology in HGPS cells, and these irregular NBs are strongly associated with cell senescence. We demonstrate that farnesylated Progerin interacts with PML isoform 2 specifically, which accounts for the formation of thread-like PML NBs. Moreover, our findings uncover that irregular PML NBs perturb NBs-associated DNA repair and gene transcription, thereby promoting HGPS cell senescence. Thus, our work helps to clarify the roles of nuclear structure and sub-compartments such as PML NBs in cell aging, and evidence presented in this study strongly support that thread-like PML NBs could be a novel biomarker of human cell senescence.
2019-09-10 | GSE137083 | GEO