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Results for “tissue specificity”

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PubMed2005

The splicing regulatory element, UGCAUG, is phylogenetically and spatially conserved in introns that flank tissue-specific alternative exons.

Previous studies have identified UGCAUG as an intron splicing enhancer that is frequently located adjacent to tissue-specific alternative exons in the human genome. Here, we show that UGCAUG is phylogenetically and spatially conserved in introns that flank brain-enriched alternative exons from fish to man. Analysis of sequence from the mouse, rat, dog, chicken and pufferfish genomes revealed a strongly statistically significant association of UGCAUG with the proximal intron region downstream of brain-enriched alternative exons. The number, position and sequence context of intronic UGCAUG elements were highly conserved among mammals and in chicken, but more divergent in fish. Control datasets, including constitutive exons and non-tissue-specific alternative exons, exhibited a much lower incidence of closely linked UGCAUG elements. We propose that the high sequence specificity of the UGCAUG element, and its unique association with tissue-specific alternative exons, mark it as a critical component of splicing switch mechanism(s) designed to activate a limited repertoire of splicing events in cell type-specific patterns. We further speculate that highly conserved UGCAUG-binding protein(s) related to the recently described Fox-1 splicing factor play a critical role in mediating this specificity.

Alternative Splicing↗

PubMed2002

Expression analysis of a family of nsLTP genes tissue specifically expressed throughout the plant and during potato tuber life cycle.

Non-specific lipid-transfer proteins (nsLTPs) are capable of binding lipid compounds in plant tissues and are coded by the nsLTP genes. Here, we present the analysis of expression of a family of potato (Solanum tuberosum) nsLTP genes that express throughout the developing plant in a highly tissue-specific manner. Three transcript-derived fragments were isolated using an amplified restriction fragment polymorphism-derived technique for RNA fingerprinting that show homology to plant nsLTP genes. These transcript-derived fragments displayed modulated expression profiles related to the development of new tissues, with a peak of transcription around the time of tuberization and just prior to sprout development, at dormancy breakage. In addition, a homologous family of expressed sequence tags was identified whose individual members could be classified according to their tissue specificity. Two subgroups of expressed sequence tags were found to express during tuber life cycle. To study the regulation of potato nsLTP genes, two putative potato nsLTP promoters were isolated and their expression was studied using promoter-marker-gene fusions. The results showed that one of the two promoters directed a highly specific pattern of expression detected in the phloem surrounding the nodes of young plants and in the same tissue of tuber related organs, whereas the second putative promoter showed little tissue or organ specificity. This difference in expression is likely due to a 331-bp insertion present in the tissue-specific promoter.

Amino Acid Sequence↗

PubMed1994

Tissue-specific variations in the expression and regulation of the small GTP-binding protein Rho.

Rho proteins are involved in the regulation of the assembly of the microfilamental cellular network and are known to be specific substrates for the ADP-ribosyltransferase C3 from Clostridium botulinum. Here, we studied the distribution of Rho and Rho-regulating proteins in extracts from various rabbit tissues. The highest amounts of [32P]ADP-ribosylated proteins were detected in cell extracts from lung and kidney. Compared to these tissues, 50-95% reduced labeling of Rho proteins was observed in extracts from liver, spleen, brain, heart and muscle. The level of the C3-mediated [32P]ADP-ribosylation of Rho did not correlate with the amount of RhoA proteins detected by Western analysis. The relative amounts of [32P]ADP-ribosylated proteins located in cytosolic or membrane fractions, respectively, depended on the type of tissue investigated, indicating a tissue-specific variation in the subcellular distribution of Rho proteins. The same was true for the complexation of Rho with other factors and the expression of diverse Rho species. In respect to Rho-regulating proteins, extracts from lung and brain contained the highest amounts of guanine nucleotide dissociation-inhibitor proteins (Rho-GDI). The association of Rho with Rho-GDI however showed tissue specificity and did not correlate with Rho-GDI amounts. The highest Rho-GAP (GAP = GTPase-activating protein) activities were observed in extracts from lung, kidney and spleen, the lowest ones in extracts from muscle and heart. In total, our data demonstrate tissue-specific differences in the expression of RhoA, [32P]ADP-ribosylated proteins and Rho-regulating factors, indicating a tissue-specific variation in the activity and regulation of Rho proteins.

Animals↗

PubMed2006

Tissue-specific expression and regulation of sexually dimorphic genes in mice.

We report a comprehensive analysis of gene expression differences between sexes in multiple somatic tissues of 334 mice derived from an intercross between inbred mouse strains C57BL/6J and C3H/HeJ. The analysis of a large number of individuals provided the power to detect relatively small differences in expression between sexes, and the use of an intercross allowed analysis of the genetic control of sexually dimorphic gene expression. Microarray analysis of 23,574 transcripts revealed that the extent of sexual dimorphism in gene expression was much greater than previously recognized. Thus, thousands of genes showed sexual dimorphism in liver, adipose, and muscle, and hundreds of genes were sexually dimorphic in brain. These genes exhibited highly tissue-specific patterns of expression and were enriched for distinct pathways represented in the Gene Ontology database. They also showed evidence of chromosomal enrichment, not only on the sex chromosomes, but also on several autosomes. Genetic analyses provided evidence of the global regulation of subsets of the sexually dimorphic genes, as the transcript levels of a large number of these genes were controlled by several expression quantitative trait loci (eQTL) hotspots that exhibited tissue-specific control. Moreover, many tissue-specific transcription factor binding sites were found to be enriched in the sexually dimorphic genes.

Animals↗

PubMed1996

Human renal cell carcinogenesis is accompanied by a coordinate loss of the tissue specific transcription factors HNF4 alpha and HNF1 alpha.

Human renal cell carcinogenesis is usually accompanied by dedifferentiation processes including the loss of expression of tissue specifically expressed genes. Based on the hypothesis that these dedifferentiation processes might be attributed to a functional change in tissue specific transcription factors, we have analyzed the expression and function of the tissue specific transcription factor HNF4 alpha in human renal cell carcinomas. By Western blot analysis and gel retardation assay using HNF4 alpha specific antibodies, we observed that in most cases the amount as well as the binding activity of HNF4 is reduced in the tumor samples compared to the corresponding normal tissues. Furthermore, we found a clear correlation between the HNF4 alpha binding activity and the amount of another transcription factor (HNF1 alpha), which is thought to be transcriptionally activated by HNF4 alpha. We therefore speculate that disruption of the HNF4 alpha/HNF1 alpha pathway of kidney specific gene expression might be an important molecular mechanism in renal cell carcinogenesis.

Antibodies, Monoclonal↗

PubMed1997

[Potential screening model for tissue specific calcium channel blockers]

Cardiovascular diseases are still the major cause of death in industrialized countries. The available therapies need improvement and specially tissue specific drugs. We have tested the possibility to establish cell lines expressing tissue specific cardiac muscular or smooth muscle L-type calcium channels. The cardiac and the smooth muscle L-type calcium channel differ in the IS6 segment of the alphaIC-gene. The established cell lines expressing the alphaIC-a or the alphaIC-b splice variants of the alphaIC-gene can be used for the screening of tissue specific calcium channel blockers.

Journal Article↗

PubMed1998

Proximal promoter region is sufficient to regulate tissue-specific expression of UDP-galactose: ceramide galactosyltransferase gene.

UDP-galactose:ceramide galactosyltransferase (CGT) is the enzyme which catalyzes the final step of the biosynthesis of galactocerebroside (GalC), the most abundant glycolipid in myelin. We identified regulatory elements which are related to the tissue-specific expression of the mouse CGT gene by promoter assay using chimeric CGT-luciferase constructs. By comparing promoter activity in oligodendroglial CG4 cells and NIH3T3 fibroblasts, only a few hundred base pairs spanning from -309 to -98 were shown to be necessary for the tissue-specific activity of CGT promoter. A negative regulatory element was found in a more distal region, from -709 to -527, and it also worked in tissue-specific manner. Sequence analysis suggests that several known elements found commonly in myelin-related genes may explain these tissue-specific regulations of the transcriptional activity.

Animals↗

PubMed2004

Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters.

Promiscuous expression of tissue-specific self-antigens in the thymus imposes T cell tolerance and protects from autoimmune diseases, as shown in animal studies. Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon. Medullary thymic epithelial cells overexpress a highly diverse set of genes (>400) including many tissue-specific antigens, disease-associated autoantigens, and cancer-germline genes. Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes. These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.

Animals↗

PubMed1987

The D-glucose transporter is tissue-specific. Skeletal muscle and adipose tissue have a unique form of glucose transporter.

Using isotopic equilibration with [3H]D-glucose and measurement of D-glucose inhibitable cytochalasin B binding, I show that the erythrocytes of embryonic and newborn rats contain D-glucose transporters. On the basis of cytochalasin B binding and the time course of isotopic exchange, the number of transporters in rat embryonic erythrocytes is only 5% of that in human erythrocytes. Antibodies raised against the human erythrocyte glucose transporter were used as a probe to investigate the structural similarity between transporters. On this basis, the polypeptides of the glucose transporter of human erythrocytes and of embryonic rat erythrocytes are similar but not identical; in addition, certain antibodies showed similar reactivity toward the transporter of rat embryonic erythrocytes and that of rat brain. These antibodies, however, react with brain transporters 5 to 10 times better than with those of skeletal muscle and adipocytes suggesting that insulin responsive tissues may have a different type of glucose transporter. The cellular location of glucose transporters in skeletal muscle, determined by immunofluorescence, is on the plasma membrane or very close to the plasma membrane.

Adipose Tissue↗

PubMed1992

Tissue-specific, developmental, hormonal, and dietary regulation of rat phosphoenolpyruvate carboxykinase-human growth hormone fusion genes in transgenic mice.

The cytosolic phosphoenolpyruvate carboxykinase (PEPCK) gene is expressed in multiple tissues and is regulated in a complex tissue-specific manner. To map the cis-acting DNA elements that direct this tissue-specific expression, we made transgenic mice containing truncated PEPCK-human growth hormone (hGH) fusion genes. The transgenes contained PEPCK promoter fragments with 5' endpoints at -2088, -888, -600, -402, and -207 bp, while the 3' endpoint was at +69 bp. Immunohistochemical analysis showed that the -2088 transgene was expressed in the correct cell types (hepatocytes, proximal tubular epithelium of the kidney, villar epithelium of the small intestine, epithelium of the colon, smooth muscle of the vagina and lungs, ductal epithelium of the sublingual gland, and white and brown adipocytes). Solution hybridization of hGH mRNA expressed from the transgenes indicated that white and brown fat-specific elements are located distally (-2088 to -888 bp) and that liver-, gut-, and kidney-specific elements are located proximally (-600 to +69 bp). However, elements outside of the region tested are necessary for the correct developmental pattern and level of PEPCK expression in kidney. Both the -2088 and -402 transgenes responded in a tissue-specific manner to dietary stimuli, and the -2088 transgene responded to glucocorticoid stimuli. Thus, different tissues utilize distinct cell-specific cis-acting elements to direct and regulate the PEPCK gene.

Adipose Tissue↗

PubMed1990

Tissue-specific expression of allogeneic class II MHC molecules induces neither tissue rejection nor clonal inactivation of alloreactive T cells.

To analyze the control of self tolerance to tissue-specific Ag, we have constructed C57BL/6 (H-2b) transgenic mice that express allogeneic class II (I-Ad) molecules exclusively on pancreatic islet cells. By a number of criteria, including I-Ad mRNA, and tissue and cell surface I-Ad protein levels, the islet cells appear to be expressing levels of I-Ad similar to B lymphocytes. Although one of the transgenic lines that expresses only the beta-chain occasionally displays slightly elevated glucose levels, this hyperglycemia is not enhanced when alpha and beta are coexpressed, allowing for cell surface I-Ad expression. None of the mice examined has demonstrated any autoimmune reaction to the I-Ad+ islet cells. Despite this apparent lack of recognition of the I-Ad+ islet cells, these animals demonstrate no reduction in the in vitro MLR generated to the same MHC molecule. Therefore, these mice remain functionally tolerant to the transgene product without inactivating those T cells that can recognize this same MHC molecule in vitro.

Animals↗

PubMed2006

Low rates of expression profile divergence in highly expressed genes and tissue-specific genes during mammalian evolution.

Evolutionary rates provide important information about the pattern and mechanism of evolution. Although the rate of gene sequence evolution has been well studied, the rate of gene expression evolution is poorly understood. In particular, it is unclear whether the gene expression level and tissue specificity influence the divergence of expression profiles between orthologous genes. Here we address this question using a microarray data set comprising the expression signals of 10,607 pairs of orthologous human and mouse genes from over 60 tissues per species. We show that the level of gene expression and the degree of tissue specificity are generally conserved between the human and mouse orthologs. The rate of gene expression profile change during evolution is negatively correlated with the level of gene expression, measured by either the average or the highest level among all tissues examined. This is analogous to the observation that the rate of gene (or protein) sequence evolution is negatively correlated with the gene expression level. The impacts of the degree of tissue specificity on the evolutionary rate of gene sequence and that of expression profile, however, are opposite. Highly tissue-specific genes tend to evolve rapidly at the gene sequence level but slowly at the expression profile level. Thus, different forces and selective constraints must underlie the evolution of gene sequence and that of gene expression.

Animals↗

PubMed1986

Lymphoid and other tissue-specific phenotypes of polyomavirus enhancer recombinants: positive and negative combinational effects on enhancer specificity and activity.

Heterologous enhancer recombinants and deletions of the polyomavirus (Py) noncoding region were constructed and analyzed for tissue specificity of DNA replication and transcription in a number of lymphoid and other cell lines. The simian virus 40 72-base-pair repeat, mouse immunoglobulin heavy-chain enhancer, and Moloney murine leukemia virus enhancer were inserted into the PvuII-D locus (nucleotides 5128 through 5265) of Py. The ability of these recombinants and the parental PvuII-D deletion mutant to replicate in permissive 3T6 cells and MOP-6 cells as well as in nonpermissive mouse B lymphoid, T lymphoid, mastocyte, and embryonal carcinoma cells was determined. Wild-type Py DNA was not permissive for replication in most lymphoid cell lines, except one hybridoma line. Simply deleting the Py PvuII-D region, however, gave Py an expanded host range, allowing high-level replication in some T lymphoid and mastocytoma cell lines, indicating that this element can be a tissue-specific negative as well as positive element. Substitution of the murine leukemia virus enhancer for Py PvuII-D yielded a Py genome which retained the ability to replicate in 3T6 cells but also replicated well in B lymphoid cells. Substitution with the immunoglobulin heavy-chain enhancer allowed replication in B lymphoid cells but interfered with replication in 3T6 cells and mastocytomas. Surprisingly, substitution with the simian virus 40 72-base-pair enhancer repeat gave a recombinant which would not replicate in any cell line tried, including MOP-6 cells, even though other recombinants with this enhancer would replicate. Thus, we observed both cooperation and interference in these combinations between enhancer components and the Py genome and that these combined activities were cell specific. These results are presented as evidence that there may be a positional dependence, or syntax, for the recognition of genetic elements controlling Py tissue specificity.

Animals↗

PubMed1985

Tissue-specific hypomethylation and expression of rat phosphoenolpyruvate carboxykinase gene induced by in vivo treatment of fetuses and neonates with 5-azacytidine.

Rat fetuses of 17-19-day gestation were injected in utero with 5-azacytidine (two to three daily injections of 40 micrograms/fetus). Neonates were injected with seven daily injections (1 mg/kg). DNA samples were isolated from the fetal and neonatal livers and neonatal spleen and subjected to analysis of their methylation status. Overall methylation was analyzed by the nearest-neighbor analysis (at CpG sites) and the pattern of methylation at CCGG sites by Southern blot analysis using phosphoenolpyruvate carboxykinase (PEPCK) sequences as probes. While DNAs from the liver and spleen undergo hypomethylation to the same extent in response to the 5-azacytidine treatment, the changes in the methylation patterns of the PEPCK gene in the two tissues are strikingly different. The changes observed indicate that a decrease in the methylase activity (inhibition by 5-azacytidine) results in site- and tissue-specific hypomethylation. The tissue-specific changes in the methylation pattern are associated with a tissue-specific expression of the PEPCK gene. Although the gene is hypomethylated by azacytidine in both liver and spleen, it is expressed only in the liver. The expression of already active genes (PEPCK in the kidney and albumin in the liver) is not further enhanced by the drug.

Animals↗

PubMed1996

Vitamin K status in human tissues: tissue-specific accumulation of phylloquinone and menaquinone-4.

We measured the vitamin K status in postmortem human tissues (brain, heart, kidney, liver, lung, pancreas) to see if there is a tissue-specific distribution pattern. Phylloquinone (K1) was recovered in all tissues with relatively high levels in liver, heart and pancreas (medians, 10.6 (4.8), 9.3 (4.2), 28.4 (12.8) pmol(ng)/g wet weight tissue); low levels (< 2 pmol/g) were found in brain, kidney and lung. Menaquinone-4 (MK-4) was recovered from most of the tissues; its levels exceeded the K1 levels in brain and kidney (median, 2.8 ng/g) and equalled K1 in pancreas. Liver, heart and lung were low in MK-4. The higher menaquinones, MK-6-11, were recovered in the liver samples (n 6), traces of MK-6-9 were found in some of the heart and pancreas samples. The results show that in man there are tissue-specific, vitamin-K distribution patterns comparable to those in the rat. Furthermore, the accumulation of vitamin K in heart, brain and pancreas suggests a hitherto unrecognized physiological function of this vitamin.

Adult↗

PubMed2001

The expanded human kallikrein (KLK) gene family: genomic organisation, tissue-specific expression and potential functions.

The tissue kallikreins are serine proteases encoded by highly conserved multi-gene families. The rodent kallikrein (KLK) families are particularly large, consisting of 13-26 genes clustered in one chromosomal locus. It has been recently recognised that the human KLK gene family is of a similar size (15 genes) with the identification of another 12 related genes (KLK4-KLK15) within and adjacent to the original human KLK locus (KLK1-3) on chromosome 19q13.4. The structural organisation and size of these new genes is similar to that of other KLK genes except for additional exons encoding 5' or 3' untranslated regions. Moreover, many of these genes have multiple mRNA transcripts, a trait not observed with rodent genes. Unlike all other kallikreins, the KLK4-KLK15 encoded proteases are less related (25-44%) and do not contain a conventional kallikrein loop. Clusters of genes exhibit high prostatic (KLK2-4, KLK15) or pancreatic (KLK6-13) expression, suggesting evolutionary conservation of elements conferring tissue specificity. These genes are also expressed, to varying degrees, in a wider range of tissues suggesting a functional involvement of these newer human kallikrein proteases in a diverse range of physiological processes.

Amino Acid Sequence↗

PubMed1996

High carbohydrate diet and starvation regulate lipogenic mRNA in rats in a tissue-specific manner.

We have previously shown that the effects of a high carbohydrate, fat-free diet and 24-h starvation on fatty acid synthesis in rats are tissue specific. In the present study we examine the tissue-specific pretranslational effects of high carbohydrate feeding, starvation and refeeding a high carbohydrate diet after starvation on the lipogenic pathway by measuring the levels of mRNA encoding acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) using Northern analysis. Additionally, we measured mRNA S14, a sequence tightly associated with lipogenesis. In rats fed the high carbohydrate diet, hepatic levels of the three mRNA were 3-5 fold higher than in controls. The level of S14 mRNA was doubled in epididymal fat, but other effects of this diet in adipose tissues were not significant. Expression in kidney, heart, lung and brain was not altered. Starvation significantly reduced the level of these mRNA in all tissues examined except brain. In liver, refeeding the high carbohydrate diet induced the expression of ACC, FAS and S14 mRNA 20-30 fold compared with the values found in 48-h starved animals. Hyperinduction of ACC and FAS, but not S14 mRNA expression was also observed in adipose tissues. The tissue-specific nature of these effects is consistent with previous measurements of fatty acid synthesis and confirm that this regulation occurs at the pretranslational level.

Acetyl-CoA Carboxylase↗

PubMed2004

Detection of tissue-specific effects by methotrexate on differentiating mouse embryonic stem cells.

BACKGROUND: Pluripotent embryonic stem (ES) cells offer a unique possibility to monitor the differentiation of several cell types in vitro. This study attempts to identify marker genes during in vitro cell differentiation of murine ES cells and allow a prediction of chemical effects on cell differentiation of specific target tissues. The study focused on the expression pattern of key genes involved in cardiomyocyte and osteoblast differentiation: Oct-4, Brachyury, Nkx2.5, alpha myosin heavy chain, Cbfa1, and Osteocalcin. METHODS: Methotrexate was selected due to its well-characterized teratogenic effects. Several in vivo studies have demonstrated the specific interactions of methotrexate with bone formation whereas the cardiovascular system is not specifically affected after exposure to low concentration. The capability of murine ES cells to differentiate in vitro into cardiomyocytes as well as into osteoblasts have been used to demonstrate the target cell specificity in vitro, at non-cytotoxic concentration. RESULTS: Exposure of differentiating ES cells did not result in any gene profile modification of the selected cardiomyocyte specific genes, whereas the expression of osteoblast specific key genes, Cbfa1 and Osteocalcin, decreased. At the latter stages of skeletal differentiation we observed a 30% decrease in gene expression for Cbfa1 and a 60% decrease for Osteocalcin, with reference to the control. Early marker genes for undifferentiated cells and mesodermal cells were not modified after methotrexate treatment. CONCLUSIONS: These results show the possibility to integrate specific in vitro tests for teratogenicity in a test strategy for developmental toxicity.

Animals↗