Specialized Transcription Factories within Mammalian Nuclei

Pombo, Ana; Jones, Emma; Iborra, Francisco J.; Kimurâ, Hiroshi; Sugaya, Kimihiko; Cook, Peter; Jackson, Dean A.

doi:10.1615/critreveukargeneexpr.v10.i1.40

Cited by 52 publications

(41 citation statements)

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“…The evidence that such factories specialize in the transcription of particular groups of genes prompts the speculation that these factories could be targeted for efficient transcription. 124 Although gene therapies have not lived up to hopes voiced for them 19 years ago, 125 research in this topic has nonetheless made a number of useful advances. Principal among these is the accurate definition of the biological hurdles that limit what is achievable and the identification of what appear to be realistic targets for our current technologies.…”

Section: Resultsmentioning

confidence: 99%

Non-viral gene delivery in skeletal muscle: a protein factory

Lu¹,

Bou‐Gharios²,

Partridge³

2003

Gene Ther

170

109

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Ever since the publication of the first reports in 1990 using skeletal muscle as a direct target for expressing foreign transgenes, an avalanche of papers has identified a variety of proteins that can be synthesized and correctly processed by skeletal muscle. The impetus to the development of such applications is not only amelioration of muscle diseases, but also a range of therapeutic applications, from immunization to delivery of therapeutic proteins, such as clotting factors and hormones. Although the most efficient way of introducing transgenes into muscle fibres has been by a variety of recombinant viral vectors, there are potential benefits in the use of non-viral vectors. In this review we assess the recent advances in construction and delivery of naked plasmid DNA to skeletal muscle and highlight the options available for further improvements to raise efficiency to therapeutic levels.

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Section: Resultsmentioning

confidence: 99%

Non-viral gene delivery in skeletal muscle: a protein factory

Lu¹,

Bou‐Gharios²,

Partridge³

2003

Gene Ther

170

109

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“…The non-coding lacO repeats were found situated in the center of the gene locus, whereas the transcribing sequences were externally positioned, as was seen from the accumulation of the polymerase, transcription factor, splicing factor and mRNAs in a flower-shaped structure surrounding the non-coding region. This structure is reminiscent of the suggested clustering of active genes into dedicated transcription factories, where they are efficiently transcribed on account of the enrichment of the necessary factors in the factory region (Iborra et al, 1996;Pombo et al, 2000;Sutherland and Bickmore, 2009).…”

Section: Discussionmentioning

confidence: 98%

The life of an mRNA in space and time

Ben-Ari

Brody

Kinor

et al. 2010

Journal of Cell Science

120

103

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SummaryNuclear transcribed genes produce mRNA transcripts destined to travel from the site of transcription to the cytoplasm for protein translation. Certain transcripts can be further localized to specific cytoplasmic regions. We examined the life cycle of a transcribed -actin mRNA throughout gene expression and localization, in a cell system that allows the in vivo detection of the gene locus, the transcribed mRNAs and the cytoplasmic -actin protein that integrates into the actin cytoskeleton. Quantification showed that RNA polymerase II elongation progressed at a rate of 3.3 kb/minute and that transactivator binding to the promoter was transient (40 seconds), and demonstrated the unique spatial structure of the coding and non-coding regions of the integrated gene within the transcription site. The rates of gene induction were measured during interphase and after mitosis, demonstrating that daughter cells were not synchronized in respect to transcription initiation of the studied gene. Comparison of the spatial and temporal kinetics of nucleoplasmic and cytoplasmic mRNA transport showed that the -actin-localization response initiates from the existing cytoplasmic mRNA pool and not from the newly synthesized transcripts arising after gene induction. It was also demonstrated that mechanisms of random movement were predominant in mediating the efficient translocation of mRNA in the eukaryotic cell.

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“…Chromatin controls the accessibility of DNA binding sites to transcription factors, influences the interactions between factors, and controls the subnuclear localization of the various proteins required for transcriptional regulation (27)(28)(29)(30). Using ChIP as a selection method, we have isolated BARX2 binding sites from accessible regions of native chromatin in MCF7 breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Binding Elements and Gene Targets for the Homeodomain Protein BARX2

Stevens

Iacovoni

Edelman

et al. 2004

Journal of Biological Chemistry

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BARX2 is a homeobox transcription factor that influences cellular differentiation in various developmental contexts. To begin to identify the gene targets that mediate its effects, chromatin immunoprecipitation (ChIP) was used to isolate BARX2 binding sites from the human MCF7 breast cancer cell line. Cloning and sequencing of BARX2-ChIP-derived DNA fragments identified 60 potential BARX2 target loci that were proximal to or within introns of genes involved in cytoskeletal organization, cell adhesion, growth factor signaling, transcriptional regulation, and RNA metabolism. The sequences of over half of the fragments showed homology with the mouse genome, and several sequences could be mapped to orthologous human and mouse genes. Binding of BARX2 to 21 genomic loci examined was confirmed quantitatively by replicate ChIP assays. A combination of sequence analysis and electrophoretic mobility shift assays revealed homeodomain binding sites within several fragments that bind to BARX2 in vitro. The majority of BARX2 binding fragments tested (14/19), also affected transcription in luciferase reporter gene assays. Mutation analyses of three fragments showed that their transcriptional activities required the HBS, and suggested that BARX2 regulates gene expression by binding to DNA elements containing paired TAAT motifs that are separated by a poly(T) sequence. Inhibition of BARX2 expression in MCF7 cells led to reduced expression of eight genes associated with BARX2 binding sites, indicating that BARX2 directly regulates their expression. The data suggest that BARX2 can coordinate the expression of a network of genes that influence the growth of MCF7 cells.

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Specialized Transcription Factories within Mammalian Nuclei

Cited by 52 publications

References 0 publications

Non-viral gene delivery in skeletal muscle: a protein factory

Non-viral gene delivery in skeletal muscle: a protein factory

The life of an mRNA in space and time

Identification of Novel Binding Elements and Gene Targets for the Homeodomain Protein BARX2

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