Epigenetic regulation of cytomegalovirus major immediate-early promoter activity in transgenic mice

Mehta, Abhishek Kumar; Majumdar, Subeer S.; Alam, Parwez; Gulati, Neerja; Brahmachari, Vani

doi:10.1016/j.gene.2008.09.033

Cited by 79 publications

(64 citation statements)

References 35 publications

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“…Alternatively, there is strong evidence supporting the notion that CMV promoter driven expression in vivo is not predictable 37 and it cannot be excluded that CMV promoter silencing occurs in the human cells transduced with the TRECMV-V14 vector, for example, through DNA methylation and histone deacetylation. 38,39 Finally, it is unlikely that an immune response against rtTA-expressing cells is taking place in the HIS (BALB-Rag/g) mice that we used in this study. Our animals are produced from immunodeficient newborn mice, which are reconstituted with immature progenitors of the human hematopoietic system expressing the rtTA protein-at low or high level depending on the vector used.…”

Section: Discussionmentioning

confidence: 99%

Autoregulatory lentiviral vectors allow multiple cycles of doxycycline-inducible gene expression in human hematopoietic cells in vivo

et al. 2009

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The efficient control of gene expression in vivo from lentiviral vectors remains technically challenging. To analyze inducible gene expression in a human setting, we generated 'human immune system' (HIS) mice by transplanting newborn BALB/c Rag2 À/À IL-2Rg c À/À immunodeficient mice with human hematopoietic stem cells transduced with a doxycyclineinducible lentiviral vector. We compared several methods of doxycycline delivery to mice, and could accurately measure doxycycline in vivo using a new sensitive detection assay. Two different lentiviral vector designs with constitutive (TRECMV-V14) or autoregulatory (TREAuto-V14) expression of an optimized reverse tetracycline transactivator were used to transduce human hematopoietic stem cells. After transplantation into immunodeficient mice, we analyzed the expression of the green fluorescent protein (GFP) reporter gene in the human hematopoiesis-derived cells that develop and accumulate in the generated HIS mice. We show efficient inducible GFP expression in adult HIS mice containing TREAuto-V14-transduced human cells, whereas GFP expression is poor with the TRECMV-V14 vector. Multiple cycles of doxycycline exposure in the TREAuto-V14 group result in repeated cycles of GFP expression with no loss of intensity. These findings are of major interest for gene therapy and basic research settings that require inducible gene expression.

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Section: Discussionmentioning

confidence: 99%

Autoregulatory lentiviral vectors allow multiple cycles of doxycycline-inducible gene expression in human hematopoietic cells in vivo

et al. 2009

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“…Although the cytomegalovirus promoter is known to induce high levels of gene expression, methylation of CpG motifs leading to gene silencing and loss of expression over time is well documented. 38,39 Therefore, if longer periods of sustained expression are required, then alternative, recently described promoters such as the mammalian b-glucuronidase minimal promoter 40 or the ubiquitous chromatin-opening element 39 may be more suitable. Furthermore, although we have looked at the levels of expression mediated by each virus in discrete areas of the brain, the actual number of viral particles in each of these areas is unknown.…”

Section: Un-injected Thresholding Intensitymentioning

confidence: 99%

In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression

et al. 2011

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The efficient delivery of genetic material to the developing fetal brain represents a powerful research tool and a means to supply therapy in a number of neonatal lethal neurological disorders. In this study, we have delivered vectors based upon adenovirus serotype 5 (Ad5) and adeno-associated virus (AAV) pseudotypes 2/5, 2/8 and 2/9 expressing green fluorescent protein to the E16 fetal mouse brain. One month post injection, widespread caudal to rostral transduction of neural cells was observed. In discrete areas of the brain these vectors produced differential transduction patterns. AAV2/8 and 2/9 produced the most extensive gene delivery and had similar transduction profiles. All AAV pseudotypes preferentially transduced neurons whereas Ad5 transduced both neurons and glial cells. None of the vectors elicited any significant microglia-mediated immune response when compared with control uninjected mice. Whole-body imaging and immunohistological evaluation of brains 9 months post injection revealed long-term expression using these non-integrating vectors. These data will be useful in targeting genetic material to discrete or widespread areas of the fetal brain with the purpose of devising therapies for early neonatal lethal neurodegenerative disease and for studying brain development.

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“…It is suggested that viral proteins target HDACs and may modulate viral and cellular gene expression (Reeves et al, 2006;SoderbergNaucier, 2006;Park et al, 2007c;Mehta et al, 2009).…”

Section: Human Cytomegalovirus and Hhv-5mentioning

confidence: 99%

Viral epigenomes in human tumorigenesis

Fernández

Esteller

2010

Oncogene

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Viruses are associated with 15-20% of human cancers worldwide. In the last century, many studies were directed towards elucidating the molecular mechanisms and genetic alterations by which viruses cause cancer. The importance of epigenetics in the regulation of gene expression has prompted the investigation of virus and host interactions not only at the genetic level but also at the epigenetic level. In this study, we summarize the published epigenetic information relating to the genomes of viruses directly or indirectly associated with the establishment of tumorigenic processes. We also review aspects such as viral replication and latency associated with epigenetic changes and summarize what is known about epigenetic alterations in host genomes and the implications of these for the tumoral process. The advances made in characterizing epigenetic features in cancer-causing viruses have improved our understanding of their functional mechanisms. Knowledge of the epigenetic changes that occur in the genome of these viruses should provide us with markers for following cancer progression, as well as new tools for cancer therapy.

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Epigenetic regulation of cytomegalovirus major immediate-early promoter activity in transgenic mice

Cited by 79 publications

References 35 publications

Autoregulatory lentiviral vectors allow multiple cycles of doxycycline-inducible gene expression in human hematopoietic cells in vivo

Autoregulatory lentiviral vectors allow multiple cycles of doxycycline-inducible gene expression in human hematopoietic cells in vivo

In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression

Viral epigenomes in human tumorigenesis

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