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PubMed2005

Controlling drug release from imprinted hydrogels by modifying the characteristics of the imprinted cavities.

The aim of this study was to analyse the influence of the template/functional monomer proportion on the achievement of molecularly imprinted hydrogels with cavities with a high enough affinity for the drug to sustain drug release. Imprinted hydrogels were prepared from N,N-dimethylacrylamide and tris(trimethylsiloxy)sililpropyl methacrylate (DMAA and TRIS; main components), methacrylic acid (MAA; functional monomer), ethylene glycol dimethacrylate (EGDMA; cross-linker), and timolol (template drug). Photo-polymerization of the monomer solutions was carried out in poly(propylene) molds (0.3 mm thickness) to obtain contact lens-like devices. Non-imprinted control hydrogels were also prepared in the same way but without the addition of timolol. The imprinted hydrogels showed a higher affinity for timolol and a slower release rate than the non-imprinted hydrogels. The release rate decreased by increasing the MAA/timolol ratio in the gel recipe. Hydrogels prepared with 400 x 10(-3) M MAA, 600 x 10(-3) M EGDMA, and a timolol/MAA mole ratio of 1:16-1:32 had drug diffusion coefficients two orders of magnitude below those of non-imprinted hydrogels. The results obtained clearly indicate that the timolol release rate is critically affected by the conditions under which the hydrogels were synthesized. These effects are discussed on the basis of the influence of drug proportion on the conformation of the imprinted cavities.

Adsorption↗
PubMed2007

Optimizing the formulation of a myoglobin molecularly imprinted thin-film polymer--formed using a micro-contact imprinting method.

Thin-film myoglobin molecularly imprinted polymers have been fabricated using a micro-contact approach. By initially selecting the cross-linker on the basis of it having a minimal recognition for the template and using this as a starting point for functional monomer selection, we have produced myoglobin imprinted polymers with exceptionally high selectivities. The affinity of the polymers, for myoglobin, when prepared with a variety of different cross-linkers and no functional monomer was evaluated. Of these, tetraethylene glycol dimethacrylate (TEGDMA) exhibited the lowest affinity for the template species. Methyl methacrylate (MMA) was chosen as the functional monomer as when it was used in conjunction with TEGDMA, it exhibited maximum selectivity for the template compared to polymers made with other functional monomers. With a MMA to TEGDMA ratio of 1 to 3, the myoglobin molecularly imprinted polymer adsorbed 15.03+/-0.89 x 10(-11)mole/cm(2) of template from a 5.68 x 10(-7)M myoglobin solution, compared to 2.58+/-0.02 x 10(-11)mole/cm(2) for a polymer of similar composition, but formed in the absence of a template. Various washing conditions, using alkaline media to remove the template, were investigated. An extraction solvent comprising 2 wt.% SDS and 0.6 wt.% NaOH used at 80 degrees C for 30 min was shown to give the highest imprinting factor i.e. 5.83 with 72.82% myoglobin removal. The saturation kinetics of template binding to the thin-film MIP were examined and found to display a simple two-phase profile typical of non-cooperative binding. A Scatchard binding plot showed the dissociation constant (K(d)) for the specific binding phase to be 3.4 x 10(-7)M and the binding site capacity to be 7.24 x 10(-11)mole/cm(2). For the non-specific binding phase, K(d) was found to be 1.355 x 10(-5)M and the binding site capacity was determined as 9.62 x 10(-10)mole/cm(2). Selectivity experiments were carried out in both single protein and binary protein systems all using a total protein concentration of 5.68 x 10(-7)M. The molar ratio of adsorbed myoglobin to IgG, HSA and hemoglobin was found to 115.5, 230.9 and 2.5, respectively. While, in binary competition systems, myoglobin selectivity to IgG, HSA and hemoglobin was, respectively, 94.18, 98.21 and 61.09%. Rebinding in natural biological matrices, i.e. human serum or urine, showed the imprinted films to have significantly greater uptake than non-imprinted films. Re-binding in undiluted urine was found to be a facile process, with the imprinting factor, i.e. the ratio of MIP to NIP binding, being determined as 37.4.

Cross-Linking Reagents↗
PubMed2002

Characterization and imprinting status of OBPH1/Obph1 gene: implications for an extended imprinting domain in human and mouse.

Human 11p15.5, as well as its orthologous mouse 7F4/F5, is known as the imprinting domain extending from IPL/Ipl to H19. OBPH1 and Obph1 are located beyond the presumed imprinting boundary on the IPL/Ipl side. We determined full-length cDNAs and complete genomic structures of both orthologues. We also investigated their precise imprinting and methylation status. The orthologues resembled each other in genomic structure and in the position of the 5' CpG island and were expressed ubiquitously. OBPH1 and Obph1 were predominantly expressed from the maternal allele only in placenta, with hypo- and not differentially methylated 5' CpG islands in both species. These results suggested that the imprinting domain would extend beyond the presumed imprinting boundary and that methylation of the 5' CpG island was not associated with the imprinting status in either species. It remains to be elucidated whether the gene is under the control of the KIP2/LIT1 subdomain or is regulated by a specific mechanism. Analysis of the precise genomic sequence around the region should help resolve this question.

Alleles↗
PubMed1993

Glutamate and imprinting memory: the role of glutamate receptors in the encoding of imprinting memory.

Glutamate-sensitive receptors have been implicated in many forms of neural plasticity and learning, including imprinting of chicks. Previous studies have indicated that glutamate binding levels in the left intermediate medial hyperstriatum ventrale (IMHV) region of the chick forebrain increase as a correlate of the acquisition of an imprinting memory; however, it has not been determined whether this is due to an increase in the number of glutamate receptors or to increased receptor affinity. The area specificity of these changes, within the left and right hemisphere, was also unexplored. We have performed Scatchard displacement binding analyses to examine changes in both the number and affinity of glutamate receptors in the left and right hyperstriatum ventrale (HV) and also the left and right archistriatal/lobus parolfactorius (AS/LPO) areas from imprinted and non-imprinted chicks. The results of this study demonstrate lateralised increases in both the number and affinity of glutamate receptors in the left HV area at 7-8 h after imprinting. Significant increases in the affinity, but not the number, of glutamate receptors were found in the left AS/LPO. This suggests that the left AS/LPO, which has previously been shown to be involved in the acquisition of a passive avoidance memory, may also be involved in the formation of an imprinting memory.

Animals↗
PubMed1997

Multiple imprinted sense and antisense transcripts, differential methylation and tandem repeats in a putative imprinting control region upstream of mouse Igf2.

The mouse insulin-like growth factor 2 (Igf2) locus is a complex genomic region that produces multiple transcripts from alternative promoters. Expression at this locus is regulated by parental imprinting. However, despite the existence of putative imprinting control elements in the Igf2 upstream region, imprinted transcriptional repression is abolished by null mutations at the linked H19 locus. To clarify the extent to which the Igf2 upstream region contains autonomous imprinting control elements we have performed functional and comparative analyses of the region in the mouse and human. Here we report the existence of multiple, overlapping imprinted (maternally repressed) sense and antisense transcripts that are associated with a tandem repeat in the mouse Igf2 upstream region. Regions flanking the repeat exhibit tissue-specific parental allelic methylation patterns, suggesting the existence of tissue-specific control elements in the upstream region. Studies in H19 null mice indicate that both parental allelic methylation and monoallelic expression of the upstream transcripts depends on an intact H19 gene acting in cis. The homologous region in human IGF2 is structurally conserved, with the significant exception that it does not contain a tandem repeat. Our results support the proposal that tandem repeats act to target methylation to imprinted genetic loci.

Alleles↗
PubMed2004

Tandem repeat hypothesis in imprinting: deletion of a conserved direct repeat element upstream of H19 has no effect on imprinting in the Igf2-H19 region.

Igf2 and H19 are reciprocally imprinted genes on mouse distal chromosome 7. They share several regulatory elements, including a differentially methylated region (DMR) upstream of H19 that is paternally methylated throughout development. The cis-acting sequence requirements for targeting DNA methylation to the DMR remain unknown; however, it has been suggested that direct tandem repeats near DMRs could be involved. Previous studies of the imprinted Rasgrf1 locus demonstrate indeed that a direct repeat element adjacent to a DMR is responsible for establishing paternal allele-specific methylation at the DMR and therefore allelic expression of the Rasgrf1 transcript. We identified a prominent and conserved direct tandem repeat 1 kb upstream of the H19 DMR and proposed that it played a similar role in imprinted regulation of H19. To test our hypothesis, we generated mice harboring a 1.7-kb targeted deletion of the direct repeat element and analyzed fetal growth, allelic expression, and methylation within the Igf2-H19 region. Surprisingly the deletion had no effect on imprinting. These results together with deletions of other repeats close to imprinted genes suggest that direct repeats may not be important for the targeting of methylation at the majority of imprinted loci and that the Rasgrf1 locus may be an exception to this rule.

Animals↗
PubMed1998

Localisation of the imprinted gene neuronatin, Nnat, confirms and refines the location of a second imprinting region on mouse chromosome 2.

Nine regions on six mouse autosomes are subject to imprinting and uniparental inheritance of any one of these regions results in mice with phenotypic anomalies. So far on distal Chromosome (Chr) 2 there is a unique imprinting region between 2H3 and 2H4 associated with two behavioural disorders and neonatal lethality. A maternally imprinted gene, Nnat, has been identified which is expressed in the nervous system and maps to distal Chr 2. Nnat has been excluded as a candidate for either or both the behavioural phenotypes as it lies proximal to the 2H3-2H4 imprinting region. Here we have mapped Nnat to band 2H1 which is at least 18 Mb proximal to the previously described imprinting region. It maps close to agouti, some alleles of which show differential expression according to parental origin. The localisation of Nnat to band H1 confirms and refines the map location of a second imprinting region on mouse Chr 2.

Animals↗
PubMed2000

Peg1/Mest locates distal to the currently defined imprinting region on mouse proximal chromosome 6 and identifies a new imprinting region affecting growth.

Mice with maternal duplication for proximal chromosome 6 (Chr 6) die in utero before 11.5 dpc, an effect that can be attributed to genomic imprinting. Previous studies have defined the region of Chr 6 responsible as lying proximal to the T6Ad translocation breakpoint in G-band 6B3. Evidence presented here with a new Chr 6 translocation T77H has substantially reduced the size of the imprinting region, locating it between G-band 6A3.2 and the centromere. The paternally expressed imprinted gene Mest had been mapped within the original imprinting region and was therefore a candidate for the early embryonic lethality. FISH has shown that Mest locates distal to T77H and therefore outside the redefined imprinting region. This evidence confirms that Mest is not a candidate for the early embryonic lethality found with two maternal copies of proximal Chr 6. Furthermore mice with maternal duplication for Ch 6 distal to T77H (MatDp.dist6) were found to be growth retarded at birth, the weight reduction remaining similar until adulthood. It can be concluded that the growth retardation is established in utero and is maintained at a similar level from birth to adulthood. Therefore Mest locates in a new imprinting region, distal to G-band 6A3.2 which affects growth. A targeted mutation of Mest has been reported that exhibits growth retardation, reduced postnatal survival and abnormal maternal behaviour. Here the phenotype of MatDp.dist6 mice is compared to that of Mest-deficient mutant mice. Unlike the latter, MatDp.dist6 mice have good survival rates and females have normal maternal behaviour. Possible reasons for these differences are discussed.

Aging↗
PubMed2006

The imprinted mouse Igf2r/Air cluster--a model maternal imprinting system.

Every diploid organism inherits a complete chromosome set from its father and mother in addition to the sex chromosomes, so that all autosomal genes are available in two copies. For most genes, both copies are expressed without preference. Imprinted genes, however, are expressed depending on their parental origin, being active on the paternal or maternal allele only. To date 73 imprinted genes are known in mouse (www.mgu.har.mrc.ac.uk/research/imprinting), 37 show paternal expression while 36 show maternal expression, indicating no bias for imprinting to occur in one sex or the other. Therefore, two different parental-specific imprinting systems may have evolved in mammals, acting specifically in the paternal or maternal gamete. Similarities and differences between the two imprinting systems will be reviewed, with specific reference to the role of non-coding RNAs and chromatin modifications. The mouse Igf2r/Air cluster is presented as a model of the maternal imprinting system.

Animals↗
PubMed1981

Neonatal imprinting and hepatic cytochrome P-450. II. Partial purification of a sex-dependent and neonatally imprinted form(s) of cytochrome P-450.

A new form of cytochrome P-450 was partially purified from hepatic microsomes of neonatally imprinted rats (adult male and adult male castrated at four weeks of age). This new form of cytochrome P-450 appears to have an apparent molecular weight of approximately 50,000 daltons as judged by sodium dodecyl sulfate polyacrylamide gel electrophoresis. It appears that this form of cytochrome P-450 is either absent or present in low concentrations in cytochrome P-450 preparations isolated from neonatally nonimprinted rats (adult female and adult male castrated at birth). Reconstitution of testosterone hydroxylase and benzphetamine N-demethylase activities of this partially purified cytochrome P-450 revealed that the presence of testosterone 16 alpha-hydroxylase activity, an imprintable microsomal enzyme, was in parallel with the imprinting status of the animals; a significantly higher activity was detected in the neonatally imprinted than that of the nonimprinted animals. This was in contrast to the nonimprintable benzphetamine N-demethylase, testosterone 7 alpha- and 6 beta-hydroxylase activities which exhibited no correlation with the imprinting status of the animals. We have prepared antisera from rabbits using the partially purified cytochrome P-450 preparations from adult male rats as antigens. These antisera inhibited microsomal testosterone 16 alpha- and 7 alpha-hydroxylase activities in a concentration-dependent manner, without impairing 6 beta-hydroxylase activity. These data suggest that the partially purified cytochrome P-450 from adult male rats consists of both imprintable (16 alpha-) and nonimprintable (7 alpha-) testosterone hydroxylase activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

The mouse H19 locus mediates a transition between imprinted and non-imprinted DNA replication patterns.

Genes subject to genomic imprinting generally occur in clusters of hundreds of kilobases. These domains exhibit several gamete of origin-dependent manifestations, including a pattern of asynchronous replication when studied by fluorescence in situ hybridization (FISH). We find a transition from asynchronous replication at the imprinted mouse H19 gene to synchronous replication at the downstream Rpl23 gene, the human homologue of which appears to be non-imprinted. Two-colour FISH demonstrates that this transition is due solely to a difference in replication timing between the upstream and downstream chromatin on the later-replicating (maternal) chromosome. This difference is lost in mice deleted for the H19 gene body and 9.9 kb of upstream DNA when this deletion is maternally inherited, with synchronous replication patterns extending over 110 kb upstream from the deleted area. No effect is seen when the deletion is paternally inherited. The presence of a boundary element in this region has been suggested by observations of position-independent expression of H19 -containing transgenes and the blocking of accessibility of downstream enhancers to the upstream Igf2 and Ins2 genes on the maternal chromosome. The FISH studies presented here demonstrate the insulation of replication patterns within the imprinted domain from downstream, non-imprinted chromatin, mediated by an element at the H19 locus which is subject to genomic imprinting.

Animals↗
PubMed2003

Preparation of ferrocyanide-imprinted pyridine-carrying microspheres by surface imprinting polymerization.

Ferrocyanide-imprinted pyridine-carrying microspheres were prepared using ferrocyanide ions as a template. This method is based on a surface imprinting technique from the seed emulsion that consisted of 4-vinylpyridine (functional monomer), styrene, and butyl acrylate and a water mixture polymerization by a radical initiator. The ferrocyanide-imprinted microspheres had about 200 times higher adsorption affinity over the non-imprinted microspheres in ferrocyanide (template) ion adsorption. This imprinted microspheres also adsorbed other tripolyphosphate, pyrophosphate, and phosphate anions much more strongly than the non-imprinted microspheres did, but were not particularly specific in ferrocyanide ion adsorption.

Journal Article↗
PubMed1998

A methylation imprint mark in the mouse imprinted gene Grf1/Cdc25Mm locus shares a common feature with the U2afbp-rs gene: an association with a short tandem repeat and a hypermethylated region.

We identified a sperm-specific methylation imprint mark (Site II) associated with a short tandem repeat sequence and a site/region methylated in both gametes (Site I) in the Grf1 locus on mouse chromosome 9, which shared a common feature with the U2afbp-rs gene. Sites or regions of gamete-specific methylation in imprinted genes are strong candidates for carrying information regarding the parental origin of alleles. The gamete-specific methylation pattern of Sites I and II was conserved after fertilization, but attained the somatic cell pattern by the blastocyst stage. In primordial germ cells, Site I was methylated, but Site II was unmethylated in both male and female embryos, suggesting that the sperm-specific methylation imprint mark in Site II was established during spermatogenesis. These common features in methylation imprint regions may be a clue to identifying regions carrying primary information for the imprinting regulation.

Animals↗
PubMed2000

A novel imprinted gene, HYMAI, is located within an imprinted domain on human chromosome 6 containing ZAC.

Transient neonatal diabetes mellitus (TNDM) is a rare disease characterized by intrauterine growth retardation, dehydration, and failure to thrive due to a lack of normal insulin secretion. This disease is associated with paternal uniparental disomy or paternal duplication of chromosome 6, suggesting that the causative gene(s) for TNDM is imprinted. Recently, Gardner et al. (1999, J. Med. Genet. 36: 192-196) proposed that a candidate gene for TNDM lies within chromosome 6q24.1-q24.3. To find human imprinted genes, we performed a database search for EST sequences that mapped to this region, followed by RT-PCR analysis using monochromosomal hybrid cells with a human chromosome 6 of defined parental origin. Here we report the identification of a novel imprinted gene, HYMAI. This gene exhibits differential DNA methylation between the two parental alleles at an adjacent CpG island and is expressed only from the paternal chromosome. A previously characterized imprinted gene, ZAC/LOT1, is located 70 kb downstream of HYMAI and is also expressed only from the paternal allele. In the pancreas, both genes are moderately expressed. HYMAI and ZAC/LOT1 are therefore candidate genes involved in TNDM. Furthermore, the human chromosome 6q24 region is syntenic to mouse chromosome 10 and represents a novel imprinted domain.

Alleles↗
PubMed2001

Imprinting and evolution of two Kruppel-type zinc-finger genes, ZIM3 and ZNF264, located in the PEG3/USP29 imprinted domain.

We have isolated Kruppel-type (C2H2) zinc-finger genes, ZIM3 (zinc-finger gene 3 from imprinted domain) and ZNF264, located downstream of human and mouse USP29 genes (encoding ubiquitin-specific processing protease 29). In human, both ZIM3 and ZNF264 encode zinc-finger proteins with Kruppel-associated box (KRAB) A and B domains at the amino-terminal regions of the predicted proteins. In contrast, mouse Zim3 and Zfp264 seem to have lost protein-coding capability based on the lack of open reading frames (ORFs) in their cDNA sequences. In particular, the 3' end of the Zim3 transcript overlaps with the coding region of the adjacent gene Usp29 in an antisense orientation, indicating the conversion of mouse Zim3 into an antisense transcript gene for Usp29. The expression patterns of ZIM3 and ZNF264 have been largely conserved between human and mouse, with testis-specific expression of ZIM3 and ubiquitous expression of ZNF264, but high expression levels in adult testes in both species. Our studies also demonstrate that both mouse genes are imprinted with maternal expression of Zim3 in adult testes and paternal expression of Zfp264 in neonatal and adult brain. The reciprocal imprinting of two neighboring mouse genes, Zim3 and Zfp264, is consistent with a pattern observed frequently in other imprinted domains, and suggests that the imprinting of these two genes might be coregulated.

Amino Acid Sequence↗
PubMed2005

Epigenetic regulation of mammalian imprinted genes: from primary to functional imprints.

Parental genomic imprinting was discovered in mammals some 20 years ago. This phenomenon, crucial for normal development, rapidly became a key to understanding epigenetic regulation of mammalian gene expression. In this chapter we present a general overview of the field and describe in detail the 'imprinting cycle'. We provide selected examples that recapitulate our current knowledge of epigenetic regulation at imprinted loci. These epigenetic mechanisms lead to the stable repression of imprinted genes on one parental allele by interfering with 'formatting' for gene expression that usually occurs on expressed alleles. From this perspective, genomic imprinting remarkably illustrates the complexity of the epigenetic mechanisms involved in the control of gene expression in mammals.

Animals↗
PubMed2003

The novel imprinted carboxypeptidase A4 gene ( CPA4) in the 7q32 imprinting domain.

By a search for novel human imprinted genes in the vicinity of the imprinted gene MEST, at chromosome 7q32, we identified the carboxypeptidase A4 gene ( CPA4) in a gene cluster of the carboxypeptidase family, 200 kb centromeric to MEST. Because CPA4 was originally identified as a protein induced in a prostate cancer cell line (PC-3) by histone deacetylase inhibitors, and was located at the putative prostate cancer-aggressiveness locus at 7q32, we investigated its imprinting status in fetal tissues and in adult benign hypertrophic prostate (BPH). RT-PCR using four intragenic polymorphisms as markers showed that CPA4 was expressed preferentially from the maternal allele in the fetal heart, lung, liver, intestine, kidney, adrenal gland, and spleen, but not in the fetal brain. It was also preferentially expressed in the BPH. These findings support that CPA4 is imprinted and may become a strong candidate gene for prostate cancer-aggressiveness. As a Silver-Russell syndrome (SRS) locus has been proposed to be located to a region near MEST and to be involved in imprinting, CPA4 would have been a candidate gene for SRS. However, analysis of ten SRS patients revealed no mutations in CPA4.

Adrenal Glands↗