When John Harley lost a friend to lupus while in medical school, he vowed to get to the bottom of the disease, a chronic autoimmune disorder that causes fatigue, joint pain, skin rashes, and sometimes death. And children infected with EBV are up to 50 times more likely to eventually develop lupus, which currently has no cure. But an explanation for the links remained elusive. The team assessed five EBV proteins. One of those, called Epstein-Barr virus nuclear antigen 2 EBNA2 , interacts with nearly half of the genetic risk loci associated with lupus in people with European ancestry, they found.
The other four EBV proteins had no interaction with the variant genes. The team then extended its analysis to include genetic risk variants associated with hundreds of illnesses beyond lupus. EBNA2 increases the risk of developing six other autoimmune diseases , the team reports today in Nature Genetics , including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. This is the first factor shown functionally to influence host gene activation mediated by any EBNA3 protein. Histone modifications and chromatin state Figure 1 showed that BMI1 associates with active enhancers and promoters, something seen previously for EBNA3 proteins 21 , 22 , H3K27me3 deposition was found to occur after establishment of repression around a handful of EBNA3A- and EBNA3C-regulated genes that have been tested in this way 9 , 10 , suggesting this histone mark is a consequence of repression at these specific loci.
Interestingly, significant co-localization was found for peaks associated with activated compared to repressed genes. However, in these time courses 3CHT was inactivated after only 21 days of active 3CHT being expressed in cells, which might not be enough for full establishment of repression.
We cannot exclude the possibility that BMI1 or SUZ12 could become important in maintenance after longer periods of continuous repression. For EBNA3C-activated genes, the consistent impairment of activation with BMI1 knockdown shown in Figure 7 is striking but could be an artefact due to the consistent difference in the starting points of gene expression between cells with or without the knockdown. BMI1 knockdown leads to increased expression of all these genes in cells grown without HT Figure 6B and 3CHT-mediated activation could seem impaired because gene expression has reached the maximum possible for these loci before the start of the time course.
This possibility was addressed by employing a conditional BMI1 knockdown that allowed testing 3CHT-mediated regulation immediately after reduction in BMI1 levels, before activation could reach a maximum. This also minimized the effects of indirect regulation at the chosen loci. The experiments presented here show that this interpretation, although reasonable at the time, is incorrect. Monoubiquitinated H2AK could not be immunoprecipitated from LCL chromatin by ChIP using four different antibodies, despite being detected by western blot, which could reflect a particular characteristic of LCLs relative to this histone modification.
There have been some studies that describe PRC1 complexes mechanistically involved in 63—66 or associated with activation 67 , They also showed that Aurora B kinase is responsible for activation in this context because it prevents H2AK ubiquitination, which is important for repression by PRC1 Since EBNA3C can repress effectively with BMI1 or SUZ12 knocked down, current available evidence suggest that histone deacetylation might be the driver for repression this study and evidence summarized in 7.
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Google Scholar. Quentin Bazot. Jonathan Lees. Paul J Farrell. Martin J Allday. Cite Citation. Permissions Icon Permissions. Open in new tab Download slide.
Search ADS. Google Preview. A model for persistent infection with Epstein-Barr virus: the stealth virus of human B cells. EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency.
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MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs. Epstein-barr virus latency in B cells leads to epigenetic repression and CpG methylation of the tumour suppressor gene Bim. Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys Histone H2A mono-ubiquitination is a crucial step to mediate PRC1-dependent repression of developmental genes to maintain ES cell identity.
Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells.
How the virus behind ‘kissing disease’ may increase your risk for autoimmune diseases like lupus
HPC3 is a new human polycomb orthologue that interacts and associates with RING1 and Bmi1 and has transcriptional repression properties. Ring1A is a transcriptional repressor that interacts with the Polycomb-M33 protein and is expressed at rhombomere boundaries in the mouse hindbrain. Novel motifs distinguish multiple homologues of Polycomb in vertebrates: expansion and diversification of the epigenetic toolkit.
Extensive co-operation between the Epstein-Barr virus EBNA3 proteins in the manipulation of host gene expression and epigenetic chromatin modification. A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Single-vector inducible lentiviral RNAi system for oncology target validation. Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains.
Antimicrob Agents Chemother. Cell Struct Funct. Altmann M, Hammerschmidt W: Epstein-Barr virus provides a new paradigm: a requirement for the immediate inhibition of apoptosis. PLoS Biol. Cancer Res. J Immunol.
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Mach M: Antibody-mediated neutralization of infectivity. Cytomegaloviruses: Molecular Biology and Immunology. Edited by: Reddehase MJ. Curr Top Microbiol Immunol.
Adv Immunol. Curr Pharm Des. J Virol Methods. Urban M, Britt W, Mach M: The dominant linear neutralizing antibody-binding site of glycoprotein gp86 of human cytomegalovirus is strain specific. Nucleic Acids Res. Download references.