PubMed · 9527998
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L P Encell, L A Loeb. 1998. One small StEP in molecular evolution.... https://doi.org/10.1038/nbt0398-234
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In this study, the physicochemical properties of polyion complex (PIC) micelles formed from antisense-oligodeoxynucleotides (antisense-ODN) and poly(ethylene glycol)-poly(L-lysine) block copolymers (PEG-PLL) were investigated to utilize them as a novel formulation for antisense-ODN delivery. Angular and concentration dependences of the diffusion coefficient of PIC micelles were evaluated by dynamic light scattering. Results suggested that the formed PIC micelles may have spherical shape with core-shell structure, in which the PIC core formed from antisense-ODN and PLL segment was surrounded by a PEG shell. The average radius of PIC micelles was dependent on the chain length of the PLL segment and was not influenced by the change in the length of ODN molecules at least in the range between 15 and 20 base pairs. Critical association concentration (cac) of PIC micelles was then determined from a profile of light scattering intensity versus concentration (Debye plots). Cac is ca. 0.20 mg/ml, which is low enough to ensure the micelle stability in very diluted condition as is the case with systemic injection into the blood compartment for antisense-ODN therapy. Furthermore, the stability of antisense-ODN against deoxyribonuclease I (DNase I) attack was evaluated using capillary gel electrophoresis, revealing that the complexation of antisense-ODN with PEG-PLL effectively prohibited DNase I attack. These characteristics of the PIC micelle system highlight its promising feature as ODN carrier used in the field of targeting therapy.
The lamin A/C gene encodes subtypes of nuclear lamins, which are involved in nuclear envelope formation, and was recently identified as the responsible gene for the autosomal dominant Emery-Dreifuss muscular dystrophy. Expression of the lamin A/C gene is developmentally regulated but little is known about the regulatory mechanism. Previous studies of lamin A/C expression suggested that the chromatin structure is important for the regulation of its expression. To elucidate the regulatory mechanism of the lamin A/C gene expression, we have analysed the functional region of the mouse lamin A/C promoter and the chromatin structure of the gene in terms of nucleosome structure and DNase I hypersensitivity. Our analyses revealed disruption of the nucleosome array at the promoter region and the presence of multiple DNase I hypersensitive sites (HSs) which were specifically associated with expression of the lamin A/C gene. Inclusion of a segment which contained the HSs in a lamin A/C promoter-luciferase reporter plasmid showed no effect on the transfected promoter activity in transient expression assays. On the other hand, substantial enhancement of the promoter activity was detected when the transfected DNA was stably integrated into the genome, suggesting the importance of the HSs in the regulation of lamin A/C expression.