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Suppressors of transcriptional transgenic silencing in Chlamydomonas are sensitive to DNA-damaging agents and reactivate transposable elements.
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Byeong-ryool Jeong Dancia Wu-Scharf Chaomei Zhang Heriberto Cerutti 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(2):1076-1081
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Rincón-Arano H Furlan-Magaril M Recillas-Targa F 《Proceedings of the National Academy of Sciences of the United States of America》2007,104(35):14044-14049
Epigenetic silencing of genes relocated near telomeres, termed telomeric position effect, has been extensively studied in yeast and more recently in vertebrates. However, protection of a transgene against telomeric position effects by chromatin insulators has not yet been addressed. In this work we investigated the capacity of the chicken beta-globin insulator cHS4 to shield a transgene against silencing by telomeric heterochromatin. Using telomeric repeats, we targeted transgene integration into telomeres of the chicken cell line HD3. When the chicken cHS4 insulator is incorporated to the transgene, we observe a sustained gene expression of single-copy integrants that can be maintained for >100 days of continuous culture. However, uninsulated single-copy clones showed an accelerated gene expression extinction profile. Unexpectedly, telomeric silencing was not reversed with trichostatin A or nicotidamine. In contrast, significant reactivation was obtained with 5-aza-2'-deoxycytidine, consistent with the subtelomeric DNA methylation status. Strikingly, insulated transgenes integrated into telomeric regions were enriched in histone methylation, such as H3K4me2 and H3K79me2, but not in histone acetylation. Furthermore, the cHS4 insulator counteracts telomeric position effects in an upstream stimulatory factor-independent manner. Our results suggest that this insulator has the capacity to adapt to different chromatin propagation signals in distinct insertional epigenome environments. 相似文献
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Gene expression and viral prodution in latently infected,resting CD4+ T cells in viremic versus aviremic HIV-infected individuals
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Chun TW Justement JS Lempicki RA Yang J Dennis G Hallahan CW Sanford C Pandya P Liu S McLaughlin M Ehler LA Moir S Fauci AS 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(4):1908-1913
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David M. Margolis 《Current infectious disease reports》2014,16(3):1-5
Antiretroviral therapy (ART) does not eliminate HIV-1 from latently infected reservoirs, and this remains the critical obstacle to the eradication of infection. Although ART is effective in suppressing viral load, life-long ART is burdensome in many respects. Given expanding numbers of HIV-infected individuals on ART worldwide, there is an urgent need to examine the possibility that innovative therapies might eradicate infection, and obviate the need for life-long medical therapy for HIV-positive people around the world. Several approaches to eradicating the latent HIV reservoir and curing infection have been proposed and are under study. An initial strategy seeks to induce the expression of the latent integrated proviral genomes within resting CD4+ T cells, so that viral proteins or particles may be revealed and allow these cellular reservoirs to be cleared. The inducing agents that have been studied recently are inhibitors of histone deacetylase (HDAC) such as suberoylanilide hydroxamic acid (SAHA). Such induction of viral expression seems unlikely in itself to efficiently clear all latently infected cells. Therefore, it seems likely that parallel efforts to augment the HIV-specific immune response with specific immunotherapies or vaccination may be required. Recently, efforts to achieve immune augmentation by ex vivo expansion of viral specific cytotoxic T-cell lymphocytes derived from HIV-infected patients have yielded an augmented HIV-specific immune response in vivo, as have cellular vaccinations delivered by administration of dendritic cells. As HIV latency and the persistence of infection despite effective ART is multifactorial, the eradication of HIV infection may require multiple approaches. 相似文献
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Components of the REST/CoREST/histone deacetylase repressor complex are disrupted, modified, and translocated in HSV-1-infected cells
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Gu H Liang Y Mandel G Roizman B 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(21):7571-7576
The infected cell protein (ICP)0 enables gene expression and the replication of herpes simplex virus (HSV)-1 in cells infected at low multiplicities and enhances the expression of genes introduced into cells by transfection or infection. We report that a short sequence of ICP0 is similar to a sequence in the amino terminus of CoREST, a corepressor that exists in complexes with the repressor REST and histone deacetylases (HDACs) 1 or 2 to repress cellular gene expression. In wild-type-virus-infected cells, HDAC1 dissociates from the CoREST/REST complex, CoREST and HDAC1 are phosphorylated by a process mediated by viral protein kinases, and CoREST and HDAC1 are partially translocated to the cytoplasm. In cells infected with a virus mutant (DeltaICP4), in which ICP0 accumulates, but post-alpha gene expression is blocked, HDAC1 is dissociated from the CoREST/REST complex, but translocation to the cytoplasm does not occur. After infection with a mutant virus from which ICP0 is deleted, the complex remains intact, but, under conditions of productive infection, the complex is partially translocated to the cytoplasm. These results suggest that, at low multiplicities of infection, ICP0 blocks CoREST-mediated silencing of viral genes by dissociation of HDAC1, whereas subsequent modifications and translocation of the components of the complex are the functions of other viral gene products made later in infection. 相似文献
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Almarza E Segovia JC Guenechea G Gómez SG Ramírez A Bueren JA 《Experimental hematology》2004,32(4):360-364
OBJECTIVE: Previous studies have shown that the HS21/45 promoter of the vav protooncogene drives a predominant expression of exogenous transgenes in mouse hematopoietic cells, including clonogenic bone marrow (BM) progenitors. We investigated the activity of this promoter in the hematopoietic stem cell compartment of adult mice. MATERIALS AND METHODS: Inbred Ly5.1 transgenic mice expressing a nonfunctional human CD4 marker gene (hCD4) under the control of the HS21/45 promoter were generated. BM cells from these animals were sorted based on the intensity of hCD4 expression. Fractions characterized by high, intermediate, or low/negative expression of the transgene were then assessed for their competitive repopulation ability (CRA), using unfractionated BM cells from Ly5.2 mice as a reference competitor population. RESULTS: Data showed that BM cells having a low/negative or intermediate expression of hCD4 had a very poor hematopoietic CRA. In contrast, BM cells with high hCD4 expression were characterized by a high CRA. These observations were confirmed in the short- and long-term posttransplantation of primary and secondary recipients when analyzing the lymphoid and myeloid cells of recipient mice. CONCLUSIONS: Our results demonstrate for the first time that the regulatory HS21/45 sequence of the vav gene constitutes an efficient promoter for driving transgene expression in multipotent hematopoietic stem cells residing in the BM of adult mice. Thus, this promoter is proposed for the development of transgenic mice and gene therapy vectors that require restricted expression of exogenous transgenes in cells of the hematopoietic system, including primitive hematopoietic stem cells. 相似文献