UBR7 an E3 ligase targets Sp110 via modulating IFN beta signalling in HBV-induced hepatic carcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE229339 | GEO | 2023/12/31
REPOSITORIES: GEO
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Project description:Plant Homeo Domain (PHD) is a versatile chromatin reader/effector module which recognizes methylated, acetylated or unmodified histone substrates and regulates cellular gene expression programs. Although PHD domains shows selective epigenetic recognition of methylated, acetylated and unmodified histone substrates, there has been no previous report on its catalytic function regulating malignant transformation of cells. Here we report that PHD finger of UBR7 (Ubiquitin Protein Ligase E3 Component N-Recognin 7 (Putative)), in isolation or in context of full length protein, harbors E3 ubiquitin ligase activity towards monoubiquitination of histone H2B at lysine 120 . Knockdown of UBR7 in MCF10a and breast cancer cells decreased H2BK120ub both at the global levels and on specific genes. Conversely, overexpression of wild type, but not catalytic mutant, rescued H2BK120ub levels. Low UBR7 expression was associated with basal-like and triple negative breast cancers as well as showed poor expression in metastatic tumors. Consistently, UBR7 loss resulted in invasion properties, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 reduced cell growth, invasion and tumor growth in mouse fat pad. Mechanistically, UBR7 reduced H2BK120ub gene body of cell-adhesion related genes as well as gene expression including on CDH4 gene. Importantly, rebuilding CDH4 levels rescued invasion phenotypes seen in UBR7-low cells. Collectively, our results establish that UBR7 PHD has novel H2B ubiquitin ligase activity and it suppresses tumor growth in basal-like breast cancers.
2019-02-08 | GSE93758 | GEO
Project description:Plant Homeo Domain (PHD) is a versatile chromatin reader/effector module which recognizes methylated, acetylated or unmodified histone substrates and regulates cellular gene expression programs. Although PHD domains shows selective epigenetic recognition of methylated, acetylated and unmodified histone substrates, there has been no previous report on its catalytic function regulating malignant transformation of cells. Here we report that PHD finger of UBR7 (Ubiquitin Protein Ligase E3 Component N-Recognin 7 (Putative)), in isolation or in context of full length protein, harbors E3 ubiquitin ligase activity towards monoubiquitination of histone H2B at lysine 120 . Knockdown of UBR7 in MCF10a and breast cancer cells decreased H2BK120ub both at the global levels and on specific genes. Conversely, overexpression of wild type, but not catalytic mutant, rescued H2BK120ub levels. Low UBR7 expression was associated with basal-like and triple negative breast cancers as well as showed poor expression in metastatic tumors. Consistently, UBR7 loss resulted in invasion properties, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 reduced cell growth, invasion and tumor growth in mouse fat pad. Mechanistically, UBR7 reduced H2BK120ub gene body of cell-adhesion related genes as well as gene expression including on CDH4 gene. Importantly, rebuilding CDH4 levels rescued invasion phenotypes seen in UBR7-low cells. Collectively, our results establish that UBR7 PHD has novel H2B ubiquitin ligase activity and it suppresses tumor growth in basal-like breast cancers.
2019-02-08 | GSE93757 | GEO
Project description:Histone chaperones modulate the stability of histones beginning from histone synthesis, through incorporation into DNA, and during recycling during transcription and replication. Following histone removal from DNA, chaperones regulate histone storage and degradation. Here we characterize UBR7 as a histone H3.1 chaperone that modulates the supply of pre-existing post-nucleosomal histone complexes. UBR7 is a largely nuclear soluble protein. We demonstrate that UBR7 binds to post-nucleosomal H3K4me3 and H3K9me3 histones via its UBR box and PHD. UBR7 binds to the non-nucleosomal histone chaperone NASP. The pool of NASP-bound post-nucleosomal histones accumulate and chromatin is depleted of H3K4me3 nucleosomes in the absence of UBR7. We propose that the interaction of UBR7, NASP, and histones opposes the histone storage functions of NASP as UBR7 promotes reincorporation of post-nucleosomal H3 complexes.
2021-12-02 | GSE183730 | GEO
Project description:Hepatitis B Virus constitutes a major threat to global public health by infecting hepatocytes, initiating and driving the progress to end-stage liver disease and liver cancer. Curing treatment for HBV infection is yet unavailable, mainly due to unmet gaps in current understanding of HBV-host interaction. Here, multi-omics interrogations were conducted to generate the first landscape of HBV-induced global changes in host transcriptome, translatome and proteome, which identified multiple translatomic events that HBV orchestrated to remodel host proteostasis networks and afford micro-environments essential for HBV proliferation and persistence.
2021-03-06 | PXD014908 | Pride
Project description:Hepatitis B virus (HBV), belonging to Hepadnaviridae family, remains undetected in early infection and is known to be the cause of several hepatic diseases leading to cirrhosis and hepatocellular carcinoma. We have found that PML-Nuclear Body Speckled 110kDa (Sp110), is hyper-expressed upon HBV infection and intriguingly, Sp110 knock-down significantly reduced viral DNA-load in the culture supernatant of HepG2.2.15 (a HBV expressing cell-line). To understand the molecular basis underlying the viral elimination upon Sp110 silencing in HepG2.2.15 cells, we performed microarray to find the differential transcriptomics in Control siRNA treated vs. Sp110 siRNA treated cells. To understand the molecular basis underlying the viral elimination upon Sp110 silencing in HepG2.2.15 cells, we performed microarray to find the differential transcriptomics in Control siRNA treated vs. Sp110 siRNA treated cells.
2019-08-24 | GSE119072 | GEO
Project description:Covalently closed circular DNA (cccDNA) forms the basis for replication and persistence of hepatitis B virus (HBV) in the chronically infected liver. In this study we sought to identify host factors interacting with the HBV genome. Nucleolin (Ncl) was identified as a potential interactor of HBV cccDNA. This interaction was veriefied using an established ChIPseq protocol. The data show that Ncl binds cccDNA albeit at lower levels than HBcAg. Ncl deposition occurs across the genome without a clear localization and a variable pattern of deposition between experiments. This verifies the interaction of Ncl with HBV-cccDNA.
2021-12-31 | GSE123715 | GEO
Project description: Not available
| S-EPMC7150939 | biostudies-literature
Project description:The newborn immune system is characterized by an impaired Th1-associated immune response. Hepatitis B virus (HBV) transmitted from infected mothers to newborns is thought to exploit the newborns’ immune system immaturity by inducing a state of immune tolerance that facilitates HBV persistence. Contrary to this hypothesis, we demonstrate here that HBV exposure in utero triggers a state of trained immunity, characterized by innate immune cell maturation and Th1 development, which in turn enhances the ability of cord blood immune cells to respond to bacterial infection in vitro. These training effects are associated with an alteration of the cytokine environment characterized by low IL-10 and, in most cases, high IL-12p40 and IFN-α2. Our data uncover a potentially symbiotic relationship between HBV and its natural host and highlight the plasticity of the fetal immune system following viral exposure in utero. RNA was extracted from 15 cord blood samples comprising of healthy cord blood monocytes (n=4), HBV-exposed cord blood monocytes (n=3), healthy cord blood plasmacytoid dendritic cells (n=4), and HBV-exposed cord blood plasmacytoid dendritic cells (n=4). Healthy adult peripheral blood monocytes (n=3) were included for comparison. The immune profile was analyzed using Nanostring and nCounter® GX Human Immunology Kit v1, comprising probes for a total of 511 immune genes.
2015-06-30 | E-GEOD-65389 | biostudies-arrayexpress
Project description:In hepatocyte nuclei, hepatitis B virus (HBV) genomes occur episomally as covalently closed circular DNA (cccDNA). The HBV X protein (HBx) is required to initiate and maintain HBV replication and acts as host gene trans-regulator. However, functionally relevant spatiotemporal localization and interactions of cccDNA and HBx remain to be understood. This is the first study utilizing circularized chromosome conformation capture (4C) to identify regional virus-host genome interactions. We combined 4C with RNA-seq and ChIP-seq to illuminate the nuclear landscape associated with HBV episomes and HBx. Moreover, we functionally studied HBx-binding to episomal HBV DNA. In human HBV-positive HepaRG hepatocytes, 4C and ChIP revealed specific nuclear localization of HBV episomes and HBx associated with actively transcribed nuclear domains correlating well in size with constrained topological units built up by chromatin fibre loops, which are believed to constitute fundamental cell nuclear architectural units. Interestingly, HBx alone occupied transcribed chromatin domains, and its binding to HBV episomes depended on its C-terminus in vitro. In conclusion, HBx and HBV DNA similarly follow higher-order nuclear assembly patterns, specifically favoring transcriptionally active nuclear compartments. These novel observations may shed light on important unsolved problems: to understand the long-term episomal stability and the facilitation of viral persistence.
2018-04-30 | GSE100400 | GEO
Project description:We found that Keap1-Nrf2 signaling pathway mediates UBR7 to regulate HK2 expression through the modification of histone H2BK120 monoubiquitination, thereby inhibiting glycolysis and HCC tumorigenesis.
2022-12-09 | GSE173454 | GEO