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Results for “Phenotypic modulation”

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PubMed1990

Modulation of sulfated proteoglycan synthesis and collagen gene expression by chondrocytes grown in the presence of bFGF alone or combined with IGF1.

Prepubertal rabbit epiphyseal chondrocytes were grown in high density primary culture for 3 d. They were then incubated for 3 additional d in serum-free culture medium to which bFGF (1-50 ng/ml) was added. During the last 24 h incubation period, either IGF1 (1-80 ng/ml) or Insulin (1-5 micrograms/ml) was added to the culture medium. Chondrocyte DNA was significantly augmented with the increasing concentration of bFGF used, thus confirming its mitogenic effect on chondrocytes. On the other hand, bFGF was also shown to modulate the phenotypic expression of the chondrocytes. The 35S-sulfate incorporation into newly synthesized proteoglycans by the cultured cells decreased in a dose-dependent manner with bFGF concentration used. In addition, chondrocyte collagen gene expression was also shown to be modulated by bFGF. Total RNA extracted from the cultured cells was analyzed by dot blot and Northern blot with cDNA probes encoding for alpha 1 II and alpha 1 I procollagen chains. A significant lower level of type II collagen mRNA, the marker of chondrocytic phenotype, was observed when cells were grown in the presence of bFGF while the level of type I mRNA remained unchanged. When IGF1 or a high concentration of insulin was added to the cells during the last 24 h of incubation with bFGF, sulfated proteoglycan synthesis, as well as collagen type II mRNA level, were significantly stimulated when compared with chondrocytes incubated with bFGF alone. In conclusion, in the present experimental conditions, bFGF appears to be a growth promoting agent for chondrocytes in vitro with dedifferentiating action on chondrocyte phenotype. IGF1 or insulin used at a high concentration can prevent the dedifferentiating effect of bFGF without inhibiting its stimulating effect on chondrocyte DNA synthesis.

Animals↗

PubMed2001

Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance.

Mutations in the DTDST gene can result in a family of skeletal dysplasia conditions which comprise two lethal disorders, achondrogenesis type 1B (ACG1B) and atelosteogenesis type 2 (AO2); and two non-lethal disorders, diastrophic dysplasia (DTD) and recessive multiple epiphyseal dysplasia (rMED). The gene product is a sulfate-chloride exchanger of the cell membrane. Inactivation of the sulfate exchanger leads to intracellular sulfate depletion and to the synthesis of undersulfated proteoglycans in susceptible cells such as chondrocytes and fibroblasts. Genotype-phenotype correlations are recognizable, with mutations predicting a truncated protein or a non-conservative amino acid substitution in a transmembrane domain giving the severe phenotypes, and non-transmembrane amino acid substitutions and splice site mutations giving the milder phenotypes. The clinical phenotype is modulated strictly by the degree of residual activity. Over 30 mutations have been observed, including 22 novel mutations reported here. The most frequent mutation, 862C>T (R279W), is a mild mutation giving the rMED phenotype when homozygous and mostly DTD when compounded; occurrence at a CpG dinucleotide and its panethnic distribution suggest independent recurrence. Mutation IVS1+2T>C is the second most common mutation, but is very frequent in Finland. It produces low levels of correctly spliced mRNA, and results in DTD when homozygous. Two other mutations, 1045-1047delGTT (V340del) and 558C>T (R178X), are associated with severe phenotypes and have been observed in multiple patients. Most other mutations are rare. Heterozygotes are clinically unaffected. When clinical samples are screened for radiologic and histologic features compatible with the ACG1B/AO2/DTD/rMED spectrum prior to analysis, the mutation detection rate is high (over 90% of alleles), and appropriate genetic counseling can be given. The sulfate uptake or sulfate incorporation assays in cultured fibroblasts have largely been replaced by mutation analysis, but may still be useful in cases where mutation analysis is not informative. Although supplementation of patients' cultured cells with thiols may bypass the transporter defect and enhance sulfation of proteoglycans, therapeutic approaches are not yet available. Mouse models for this and other disorders of sulfate metabolism are being developed to help in developing therapeutic treatments.

Animals↗

PubMed2006

Tumor-microenvironment interactions: the selectin-selectin ligand axis in tumor-endothelium cross talk.

Interactions of cancer cells with components of their microenvironment are crucial determinants in the decision making process which determines whether the cancer cells will progress towards a highly malignant phenotype or whether they will stay dormant or disappear altogether. The tumor microenvironment is composed of a plethora of soluble and cellular components. Many of these components deliver signals to tumor cells and thus modulate their phenotype thereby driving tumor progression. This chapter focuses on the interaction of tumor cells with endothelial cells through endothelial selectins and their fucosylated ligands expressed by the tumor cells. Comparisons are drawn between the utilization of this interaction axis by inflammatory leukocytes and by tumor cells.

Cell Communication↗

PubMed1997

Biosynthesis of sulfated extracellular matrices by alveolar type II cells increases with time in culture.

The aim of this study was to determine the extent to which sulfate incorporated into biosynthesized basement membrane (BM) components increased as isolated type II cells progress toward a more type I cell-like phenotype from 7 to 21 days in culture. Specific sulfate cytochemistry, using high iron diamine, showed that type I-like cells in 21-day cultures deposited a more highly sulfated extracellular matrix. Biosynthetic labeling experiments using [35S]cysteine or [35S]sulfate as precursors confirmed the increased capacity of 21-day type I-like cells to biosynthesize sulfated BM components compared with type II-like cells in 7-day cultures, including a novel sulfated laminin. These biochemical changes in sulfation of BM components coincide with the established phenotypic transition from type II to type I cells during prolonged culture. More importantly, the data suggest that regulation of sulfation constitutes a potential mechanism by which type I and type II cells alter their environment in such a manner as to stabilize phenotype and modulate responses to growth factors.

Animals↗

PubMed2006

The unusual genetics of human longevity.

In no species other than humans do cultural, social, and biological factors interact with each other in modulating complex phenotypes. Thus, the identification of genetic factors that affect human longevity is a true challenge. The model of centenarians provides us a unique opportunity to tackle this challenge. In this Perspective, we discuss some recent findings (the impact of geography and demography on the longevity phenotype, the relationship between longevity and homozygosity, the role of the nuclear-mitochondrial genome cross-talk) by which new ideas are suggested, such as the concept of a complex allele timing as a pivotal process in modulating the probability of achieving longevity.

Demography↗

PubMed1987

The influence of extracellular matrix on gene expression: is structure the message?

The study of the regulation of gene expression in cultured cells, particularly in epithelial cells, has been both hampered and facilitated by the loss of function that accompanies culture on traditional plastic substrata. Initially, investigations of differentiated function were thwarted by the inadequacy of tissue culture methods developed to support growth of mesenchymal cells. However, with the recognition that the unit of function in higher organisms is larger than the cell itself, and that gene expression is dependent upon cell interactions with hormones, substrata and other cells, came the understanding that the epithelial cell phenotype is profoundly influenced by the extracellular environment. In the last decade research on epithelial cells has centred on culture conditions that recreate the appropriate environment for function with very promising and important results. The investigations into the modulation of phenotype in culture produced not only a better model, but also contributed to a better understanding of the regulation of normal function. Using cultured mammary gland epithelial cells as a primary model of these interactions, our studies of gene expression are based on three premises. (1) That the extracellular matrix (ECM) on which the cells sit is an extension of the cells and an active participant in the regulation of cellular function; i.e. the ECM is an 'informational' entity in the sense that it receives, imparts and integrates structural and functional signals. (2) That ECM-induced functional differentiation in the mammary gland is mediated through changes in cell shape, i.e. that the structure is in large part 'the message' required to maintain differentiated gene expression. (3) That the unit of function includes the cell plus its extracellular matrix; in a larger context, the unit is the organ itself. These tenets and the data presented below are consistent with a model of 'Dynamic Reciprocity', where the ECM is postulated to exert an influence on gene expression via transmembrane proteins and cytoskeletal components. In turn, cytoskeletal association with polyribosomes affects mRNA stability and rates of protein synthesis, while its interaction with the nuclear matrix could affect mRNA processing and, possibly, rates of transcription.

Animals↗

PubMed1994

Genetic approaches to understanding the pathophysiology of complex human traits.

Genetic approaches to understanding the pathophysiology of complex human traits, for example, hypertension, can complement physiologic analyses and are likely to improve our ability to treat or prevent the disease. A particularly useful approach is to perform linkage analysis with candidate genes using intermediate phenotypes. This has proven successful so far in identifying two genes involved in hypertension. The first was a fusion gene mutation which linked the regulatory region of the 11B-hydroxylase gene to the coding sequence for the protein of aldosterone synthetase. This mutant gene is responsible for the condition glucocorticoid-remediable aldosteronism (GRA). The intermediate phenotype used was increased levels of the adrenal steroids 18-oxo and hydroxycortisol. The gene for GRA was identified using a pedigree approach. It is likely, to identify other genes in hypertension, that the most appropriate population to be affected would be sib pairs, that is, sibling pairs who both have hypertension. In a recent study the angiotensinogen gene also was linked to hypertension in individuals who had severe or early onset hypertension. In addition, a variant of the angiotensinogen gene, substitution of threonine rather than methionine at codon 235, was specifically associated with hypertension. In a separate study, the T235 homozygote of the angiotensinogen gene was associated with the non-modulating intermediate phenotype of essential hypertension. Since converting enzyme inhibitors appear to correct the specific defect underlying the elevated blood pressure in non-modulators, identification of the gene potentially associated with non-modulation raises the strong possibility that genetic screening will allow for more specific therapy.

Alleles↗

PubMed2005

A functional SNP in the promoter region of TCOF1 is associated with reduced gene expression and YY1 DNA-protein interaction.

Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial malformation caused by null mutations in the TCOF1 gene. High inter and intra familial clinical variability, ranging from mild malar hypoplasia to perinatal death due to airway collapse is observed, but, to date, no genotype-phenotype correlation has been reported. Considering haploinsufficiency as the molecular mechanism underlying the disease, we have hypothesized that mutations in the promoter region of the gene, which has never been previously characterized, in trans with a pathogenic mutation, could modulate the phenotype. Therefore, the aims of the present study were to determine the TCOF1 gene's core promoter and to identify mutations in this region that could contribute to the phenotypic variation observed in this syndrome. We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. We screened 1.2 kbp of the TCOF1 5' flanking sequence in the DNA obtained from 21 patients and 51 controls and identified four new single nucleotide polymorphisms (SNPs), one of which (-346C>T), was proved to be functional, as it decreased the promoter activity by 38%. Electrophoretic mobility shift assay (EMSA) analysis demonstrated that the -346T allele impairs DNA-binding to the YY1 transcription factor. This promoter variant represents a candidate allele to explain the clinical variability in patients bearing TCS.

Alleles↗

PubMed2005

Emerging concepts in GPCR function--the influence of cell phenotype on GPCR pharmacology.

G protein coupled receptors (GPCRs) are an important class of ligand-activated proteins that regulate cellular metabolism. It is now appears that GPCR function is highly dependent upon the cellular environment in which it is expressed. Indeed, the cell phenotype influences several sequelae of GPCR activation, including GPCR oligomerization, G protein coupling, spatial organization of signaling proteins and inactivation and internalization processes. The cell phenotype, consequently, modulates both the affinity and efficacy of endogenous agonists and synthetic compounds. Emerging data suggests a complex function of GPCR signaling resulting in tissue specific responses, even those emanating from the same GPCR subtype. This short review describes some phenotypic influences on GPCR function and their implications for the use of cell-based assays used to identify and characterize GPCR ligands.

Animals↗

PubMed1991

Physical, Chemical, Developmental, and Genetic Factors that Modulate the Agrobacterium-Vitis Interaction.

Tumor formation in Vitis species and hybrids, incited by Agrobacterium tumefaciens, was altered by chemical, physical, developmental, and genetic variables. Knowledge of the effect of these variables was used to develop a stringent in vitro assay system to select parents for a study of genetic factors that modulate tumor formation. Tumor formation was reduced by short day preconditioning of assay plants and by inoculation of the morphological apex of isolated stem segments. Pretreatment of plants with auxin or cytokinin altered specificity in various combinations of strains and host genotypes. All Vitis species and hybrids formed tumors in response to strains designated as limited host range, but some displayed a necrotic reaction (cell death at and below site of inoculation) or a null response (same as the response to inoculation with an avirulent strain) to strains designated as wide host range (VC Knauf, CG Panagopoulos, EW Nester [1982] Phytopathology 72: 1545-1549). Screens of F(1) progeny, derived from crosses of null, necrotic, and tumor-producing phenotypes, demonstrated that the null and the necrotic phenotypes were modulated by dominant and recessive host genes. The extent of cellular necrosis in the necrotic phenotype was modified by the morphological location of the inoculation site, by the presence of buds on the host stem, and by deletion of the tryptophane monooxygenase locus gene of the Ti-plasmid.

Journal Article↗

PubMed2026

Complex genotype-phenotype relationships in neurodevelopmental disorders.

With the advent of sequencing technologies in recent years, hundreds of high-confidence risk genes have been implicated in neurodevelopmental disorders (NDDs). However, individuals carrying pathogenic variants in the same gene frequently exhibit diverse clinical presentations, including varied symptoms and diagnoses. We propose that this heterogeneity arises from different interacting factors that modulate the phenotypic outcomes of pathogenic variants, including variant-level features, modifying variation across the genome, prenatal and early-life environmental exposures, and developmental noise. Resolving these factors requires integrative approaches that combine population-scale genetics and functional genomics with environmental monitoring and quantitative assessments of stochastic developmental variation. Advancing our understanding of these factors is critical to elucidating the etiology of NDDs and improving diagnostic and personalized therapeutic strategies.

Humans↗

PubMed2003

Genetic epistasis of adiponectin and PPARgamma2 genotypes in modulation of insulin sensitivity: a family-based association study.

AIMS/HYPOTHESIS: Genetic interactions in modulating the phenotypes of a complex trait, such as insulin sensitivity, were usually taken for granted. However, this has not been commonly shown. Previous studies have suggested that both PPARgamma2 and adiponectin genes could influence insulin sensitivity. Therefore it is likely that they could modulate insulin sensitivity through gene to gene interactions. METHODS: We genotyped 1793 subjects of Chinese and Japanese descendents from 601 hypertensive families recruited in Sapphire study for a T94G in the adiponectin gene exon 2 and the PPARgamma2 Pro12Ala polymorphisms. Serum insulin concentrations and insulin resistance index (HOMA(IR)) were used as the markers of insulin sensitivity. RESULTS: We found that the T allele of adiponectin gene was associated with a higher Ins60 and higher area under curve of insulin (AUCi) in OGTT utilizing all subjects in a mixed model that corrected for family effects. Important interactions between adiponectin and PPARgamma2 genotypes were found in fasting insulin concentrations (Ins0), insulin concentrations at 2-h (Ins120) in OGTT and insulin resistance index (HOMA(IR)). The main effects of the PPARgamma2 genotypes were in the plasma glucose concentrations in OGTT. In contrast, the main effects of adiponectin genotypes were in every insulin variable, including Ins0, Ins60, Ins120, AUCi and HOMA(IR). The subjects carrying the adiponectin G allele and the PPARgamma2 Ala12 allele seemed to be more insulin sensitive. CONCLUSION/INTERPRETATION: These results showed that adiponectin is a genetic factor associated with insulin sensitivity. Interactions with PPARgamma2 genotypes modified this association.

Adiponectin↗

PubMed1997

A sex-influenced modifier in Drosophila that affects a broad spectrum of target loci including the histone repeats.

A second chromosomal trans-acting modifier, Lightener of white (Low), modulates the phenotypic expression of various alleles of the white eye color gene. This modifier has an unusually broad spectrum of affected genes including white, brown, scarlet and the eye developmental genes, Bar and Lobe. In addition, Low weakly suppresses position effect variegation. Northern blot hybridization with different X and autosomal probes reveals that Low modulates genes of independent expression patterns. Interestingly, many of the modulations of gene expression are developmentally restricted and differ in intensity between the sexes. Low also elevates the expression of the histone tandem repeats in three distinct developmental stages. A deficiency encompassing the histone cluster reduces their transcript levels and significantly alters the expression of some of the tested genes. Thus, Low is a modifier that plays a role in modulating the expression of genes governing various processes including pigment deposition, eye development, chromosomal proteins and position effect variegation.

Alleles↗

PubMed1998

Phenotypic variation in heterozygous familial hypercholesterolemia: a comparison of Chinese patients with the same or similar mutations in the LDL receptor gene in China or Canada.

Familial hypercholesterolemia (FH) is caused by mutations in the LDL receptor (LDLR) gene and is usually associated with hypercholesterolemia, lipid deposition in tissues, and premature coronary artery disease (CAD). However, individuals with heterozygous FH in China exhibit a milder phenotype despite having deleterious mutations in the LDLR gene (X.-M. Sun et al, Arterioscler Thromb. 1994;14:85-94). Nineteen Chinese FH heterozygotes living in Canada were screened for the 11 mutations that had been described in FH patients living in China. One Chinese Canadian carried one of these mutations (Trp462Stop), 2 carried a previously unreported single-base substitution (Cysl63Arg), and 1 carried a mutation observed in French-Canadian patients (Glu207Lys). Twelve additional carriers of these mutations were identified in the families of the index patients. Significantly higher LDL cholesterol concentrations were observed in FH heterozygotes with defined mutations living in Canada (mean+/-SD, 7.46+/-1.29, n=16) than in those living in China (4.35+/-1.09, n=18; P<.0001). Six of the 16 FH heterozygotes residingin Canada had evidence of tendon xanthomata and 4 had a history of premature CAD, whereas none of those in China had tendon xanthomata or CAD. Complete segregation between hypercholesterolemia and inheritance of a mutant allele was observed in 3 Canadian Chinese FH families. Thus, Chinese FH heterozygotes living in Canada exhibit a phenotype similar to that of other FH patients in Western societies. The difference between patients living in Canada and those living in China could be ascribed to differences in dietary fat consumption, showing that environmental factors such as diet play a significant role in modulating the phenotype of heterozygous FH.

Adult↗

PubMed1991

Phenotypic plasticity of Schwann cells and enteric glial cells in response to the microenvironment.

We produced earlier a monoclonal antibody against Schwann cell myelin protein (SMP), a glycoprotein expressed on Schwann cells (SC) but not on satellite cells of the ganglia or enteric glial cells. We now studied whether SMP expression is environmentally regulated in the different compartments of the peripheral nervous system. Quail neural-crest cells from either mes-metencephalic, vagal, or truncal levels of the neuraxis were heterochronically associated with gut wall, skin, or muscle tissues from embryonic day (E) 7 to E11 chickens. Coculture of these chimeric organs revealed that as in normal development glial cells, characterized by HNK1 immunoreactivity and the quail nuclear marker, expressed the SMP phenotype exclusively in skin and muscle, failing to do so in gut. However, when SMP+ SC from quail sciatic nerves were cocultured with chicken gut, these cells rapidly lost their initial SMP immunoreactivity. In contrast, when associated with muscle and skin, SC remained SMP+, even in the complete absence of neuronal cells. Enteric plexuses from E8 to E15 quail gut express SMP+ and laminin when withdrawn from the intestinal-mesenchyme environment. These results show that SMP can be expressed by enteric glial cells and that the SC SMP phenotype is strongly inhibited by the gut-wall environment. Moreover, these results strongly suggest that these two types of glial cells belong to the same lineage and that their terminal phenotype is modulated through cell-to-cell interactions.

Animals↗

PubMed2000

Periosteally derived osteoblast-like cells differentiate into chondrocytes in suspension culture in agarose.

Pluripotent cells from the periosteal layer adjacent to cortical bone attain an osteoblast-like phenotype in culture when reaching confluence in monolayer. It is unknown whether such newly differentiated osteoblast-like cells preserve the chondrogenic potential characteristics for stem cells derived from the periosteum. Primary osteoprogenitor cells derived from bovine metacarpal periosteum were differentiated into alkaline phosphatase-positive osteoblast-like cells by an established monolayer culture protocol. After transfer into suspension culture in agarose gels, the cells differentiated into chondrocytes demonstrated by the production of collagen II, but not of collagen I, as well as alkaline phosphatase activity was abated. Contrarily, with continuation of monolayer culture, the cells maintained their osteoblast-like phenotype and secreted large amounts of collagen I and a minor quantity of collagen III and V. The alkaline phosphatase activity steadily increased during the entire culture period of 2 weeks. Thus, our culture techniques can serve as useful tools to study mechanisms of differentiation by modulating the phenotypic potential of osteogenic cells. The results presented here support the notion that the extracellular environment strongly influences the cell type and its metabolism.

Alkaline Phosphatase↗

PubMed1991

Calponin. Developmental isoforms and a low molecular weight variant.

Two-dimensional gel analysis of basic proteins in developing human smooth muscle identifies calponin as a prominent marker of the differentiated phenotype. Adult tissue (human and mouse) typically expresses up to four calponin isoforms, three of which appear sequentially during fetal development: adult myometrial cells express the same three isoforms in primary culture in vitro and these are down-regulated, in reverse order, during the subsequent modulation of phenotype. Monospecific, polyclonal antibodies against calponin identify a lower molecular weight variant of calponin (L-calponin) that is strongly and specifically expressed in adult smooth muscles of the human urogenital tract. L-calponin is down-regulated in benign smooth muscle derived tumors (leiomyoma) and is not expressed in primary cultures of normal uterine tissue.

Animals↗

PubMed1997

Determinants of fetal hemoglobin response to hydroxyurea.

Fetal hemoglobin (HbF) modulates the phenotypic diversity of sickle cell anemia (HbSS), and the prevalence of many disease complications is related to the level of HbF. Hydroxyurea (HU) increases HbF levels in many patients. Adults with HbSS have HbF levels that may differ by two orders of magnitude, suggesting the possibility of genetic modulation of gamma-globin gene expression. In HbSS, the beta-globin gene haplotype is associated with HbF. Polymorphisms present in cis-acting elements are usually linked to the haplotype, suggesting that within a haplotype, mutations in these areas are uncommon mechanisms of HbF modulation in patients with untreated HbSS. In a multicenter trial of HU in HbSS, we examined genetic elements, patient characteristics, and follow-up features to determine their association with changes in HbF. Following treatment, F cells increased in HU-treated patients compared with controls. The increases in the HbF level at 2 years were greatest in patients who had the highest baseline counts of reticulocytes and neutrophils, two or more episodes of study-defined myelotoxicity, and absence of a Bantu haplotype. However, after 2 years, half of the patients had no or only trivial increments in HbF. The ability to respond to HU may depend on bone marrow reserve, or the capacity of the marrow to withstand moderate doses of HU with acceptable myelotoxicity. Baseline reticulocyte and neutrophil counts may be a measure of this marrow reserve. Sustained HbF increases during HU treatment can occur in individuals with bone marrow reserve sufficient to respond to the myelotoxicity of this agent with the evolution of a population of high HbF-producing erythroblasts.

Adult↗