Expression of a Foreign Gene in a Line of Transgenic Mice Is Modulated by a Chromosomal Position Effect

Al‐Shawi, Raya; Kinnaird, Jane; Burke, J; Bishop, John O.

doi:10.1128/mcb.10.3.1192-1198.1990

Cited by 11 publications

(6 citation statements)

References 42 publications

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“…This squares with evidence that nickel compounds are carcinogenic yet show no mutagenicity in mammalian cell assays. It is well established that chromosomally integrated transgenes in transfected cell lines and transgenic animals are susceptible to inactivation by changes in chromatin structure, thus revealing that chromatin structural change is a potential mechanism of transcriptional regulation − .…”

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confidence: 99%

Heterochromatinization as a Potential Mechanism of Nickel-Induced Carcinogenesis

Ellen

Kluz²,

Harder³

et al. 2009

Biochemistry

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Epigenetics refers to heritable patterns of gene expression that do not depend on alterations of the genomic DNA sequence. Nickel compounds have demonstrated carcinogenicity without any associated mutagenesis, suggesting that its mechanism of carcinogenesis is epigenetic in nature. One such potential mechanism is the heterochromatinization of chromatin within a region of the genome containing a gene sequence, inhibiting any further molecular interactions with that underlying gene sequence and effectively inactivating that gene. We report here the observation, by atomic force microscopy and circular dichroism spectropolarimetry, that nickel ion (Ni 2+ ) condenses chromatin to a greater extent than the natural divalent cation of the cell, magnesium ion (Mg 2+ ). In addition, we use a model experimental system that incorporates a transgene, the bacterial xanthine guanine phosphoribosyl transferase gene (gpt) differentially near to, and far away from, a heterochromatic region of the genome, in two cell lines, the Chinese hamster V79-derived G12 and G10 cells, respectively, to demonstrate by DNase I protection assay that nickel treatement protects the gpt gene sequence from DNase I exonuclease digestion in the G12 cells, but not in the G10 cells. We conclude that condensation of chromatin by nickel is a potential mechanism of nickel-mediated gene regulation. Keywords chromatin; heterochromatin; nickel; divalent cation; carcinogenesisChromatin is the natural state of protein-associated DNA in all eukaryotes. It is a dynamic polymer of subunits called nucleosomes. The nucleosome subunit consists of approximately 146 bps of DNA wrapped around an octamer of histone proteins. The histone octamer is made up of two each of histone H2A, H2B, H3, and H4. The DNA makes one and a half turns around the octamer, with the entry and exit points of the DNA at opposite sides of the disk-shaped histone octameric complex. This complex of 146 bps and the octamer of histones is known as the nucleosome core particle. In chromatin, the exiting and entering DNA duplex strands of this nucleosome core particle extend to the next nucleosome core particles on either side of it. The intervening DNA connecting each pair of nucleosomes is termed the linker DNA. The lengths of these intervening DNA duplex strands vary from species to species and from tissue types to tissues types, as well as from one stretch between two nucleosomes to another. Linker DNA length ranges from a minimum of 25 bps to upwards of 100 bps, averaging approximately 50 to 60 bps (1). A fifth histone type, the linker histone (H1), binds to the linker DNA in a stoichiometry of 1 H1 to 1 nucleosome. The complex of the core particle (the histone octamer

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confidence: 99%

Heterochromatinization as a Potential Mechanism of Nickel-Induced Carcinogenesis

Ellen

Kluz²,

Harder³

et al. 2009

Biochemistry

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“…Quantitative analysis of integrated green fluorescent protein ( Gfp ) genes showed that integrated copies of the transgene were highest in the 13-line ( Figure 1 B). However, the amount of integrated transgene is not proportional to its expression level because the exogenous transgene is affected by the site of chromosomal integration [ 25 , 26 ]. Therefore, we analyzed the expression of Npgl mRNA in the mediobasal hypothalamus (MBH).…”

Section: Resultsmentioning

confidence: 99%

Neurosecretory Protein GL Promotes Normotopic Fat Accumulation in Male ICR Mice

Narimatsu

Matsuura

Furumitsu

et al. 2022

IJMS

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Neurosecretory protein GL (NPGL) is a small secretory protein identified in the hypothalamus of birds and mammals. We recently reported that NPGL exerts obesogenic effects in obesity-prone C57BL6/J mice. However, whether NPGL elicits adiposity in different mouse strains is poorly understood. In this study, we generated transgenic mice overexpressing Npgl using the ICR strain (Npgl Tg mice) to elucidate the obesogenic effects of NPGL in different strains. Npgl Tg mice showed increased white adipose tissue (WAT) mass. Although the mass of brown adipose tissue (BAT) was slightly altered in Npgl Tg mice, hypertrophy of lipid droplets was also observed in BAT. In contrast, fat accumulation was not induced in the liver, with the upregulation of mRNAs related to hepatic lipolysis. These results support the hypothesis that NPGL causes obesity in several strains and species. This report highlights the pivotal role of NPGL in fat accumulation in adipose tissues and contributes to the elucidation of the biological mechanisms underlying obesity and metabolic diseases in heterogeneous populations.

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“…BS6-tk-supF (TR) contains two copies of BS6-tk-supF, each lacking a short 5' region and separated by a 500-bp fragment of mouse DNA, which were integrated at a single chromosomal site in a line of transgenic mice (2, 27a). The complete tandem dimer together with flanking DNA sequences was recovered from two bacteriophage lambda clones and reintroduced into the mouse genome (2). These constructs displayed different patterns of tissue-specific expression (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…2A and C, lane 1) and must therefore be a reverse transcript, possibly related to a reverse transcript previously observed in cells infected with HSV-1 (18, 25). Line L78 carries a full-length copy and a second truncated copy of the 5' end of the BS6-tk-supF gene (2). L78 uniquely has a third short (500-bp) testis transcript (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Herpes Simplex Virus Type 1 Thymidine Kinase Is Expressed in the Testes of Transgenic Mice under the Control of a Cryptic Promoter

Al‐Shawi

Burke

Wallace

et al. 1991

Molecular and Cellular Biology

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We reported previously that the herpes simplex virus type 1 (HSV-1) thymidine kinase reporter gene (tk) was expressed in the testes of transgenic mice when coupled to the promoter of a liver-specific mouse major urinary protein (MUP) gene. Here we show that HSV-1 tk is also expressed in the testis when coupled to a MUP pseudogene promoter, to a truncated MUP promoter that is not active in the liver, and to the promoter of the bovine thyroglobulin gene. Furthermore, HSV-1 tk itself was expressed in the testis, although its normal expression had been disabled by removing an upstream regulator of transcription. In every case, the same multiple transcripts were observed, with their 5' ends located downstream of the normal HSV-1 tk translation initiation codon. We conclude that the transcription of HSV-1 tk in the testis is directed by a cryptic TATA box-independent promoter located in the coding region of the gene. The longest HSV-1 thymidine kinase (TK) polypeptides synthesized in the testis were shorter than full-length TK and probably result from translational initiation at Met46 and Met60, the second and third ATG codons of the tk reading frame. Male mice of most transgenic lines were sterile, and the severity of the lesion in spermatogenesis was directly related to the level of TK expression. In the most highly expressing lines, sperm counts were low and morphologically defective sperm were common. In other sterile lines, TK was expressed at a lower level and sperm counts were normal but sperm motility was greatly reduced. Lines with the lowest levels of HSV-1 TK expression were fertile. HSV-1 TK was expressed in germ line cells, mainly in the haploid spermatids. However, low-level HSV-1 TK activity was found in the testis before the first germ cells entered meiosis, showing that if expression is confined to the germ cells, it also occurs in spermatogonia.

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Expression of a Foreign Gene in a Line of Transgenic Mice Is Modulated by a Chromosomal Position Effect

Cited by 11 publications

References 42 publications

Heterochromatinization as a Potential Mechanism of Nickel-Induced Carcinogenesis

Heterochromatinization as a Potential Mechanism of Nickel-Induced Carcinogenesis

Neurosecretory Protein GL Promotes Normotopic Fat Accumulation in Male ICR Mice

The Herpes Simplex Virus Type 1 Thymidine Kinase Is Expressed in the Testes of Transgenic Mice under the Control of a Cryptic Promoter

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