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PubMed2005

Construction of a combined physical and genetic map of the chromosome of Lactobacillus acidophilus ATCC 4356 and characterization of the rRNA operons.

The combination of PFGE and hybridization approaches was used to study the genome of Lactobacillus acidophilus neotype strain ATCC 4356. PFGE analysis of chromosomal DNA after digestion with each of the rare-cutting restriction enzymes I-CeuI, NotI, CspI, SmaI, ApaI and SgrAI allowed the size of the circular chromosome of L. acidophilus to be estimated at 2.061 Mbp. The physical map contained 86 restriction sites for the six enzymes employed, with intervals between the sites varying from 1 to 88 kbp (approximately 0.05-4.3 % of the chromosome). Based on the physical map, a genetic map was constructed via Southern blot analyses of L. acidophilus DNA using specific gene probes. A total of 73 probes representing key genes, including 12 rRNA (rrn) genes, were positioned on the latter map. Mapping analysis also indicated the presence of four rrn operons (rrnA-D) on the chromosome, each containing a single copy of each of the three rrn genes 16S (rrl), 23S (rrs) and 5S (rrf). Operon rrnD was inverted in orientation with respect to the others and contained a long 16S-23S intergenic spacer region with tRNAIle and tRNAAla genes, whereas the other operons contained a short spacer lacking any tRNA genes. The high-resolution physical/genetic map constructed in this study provides a platform for genomic and genetic studies of Lactobacillus species and for improving industrial and probiotic strains.

Chromosome Mapping↗

PubMed2005

Aberrant gene silencing in tumor progression: implications for control of cancer.

Although it is clear that genetic alterations are critical for the initiation and maintenance of human cancer, it is also becoming evident that epigenetic changes may be essential for the development of these diseases as well. The best studied of these latter processes is heritable transcriptional repression of genes associated with aberrant DNA hypermethylation of their promoters. Herein we review how very early occurrence of these gene silencing events may contribute to loss of key gene functions which result in disruption of cell regulatory pathways that may contribute to abnormal cell population expansion. These altered regulatory events may then provide a setting where mutations in the same disrupted pathways may be readily selected and serve to lock tumor progression into place. This hypothesis has potential impact on means to prevent and control cancer and for the use of epigenetic markers for cancer risk assessment and early diagnosis.

Animals↗

PubMed2002

Perspective: the ovarian kaleidoscope database-II. Functional genomic analysis of an organ-specific database.

In the postgenomic era, it is now possible to investigate the function of all human genes to provide an integrated view of physiology and pathophysiology. An organ-based approach has been used to set up a database integrating existing text-based literature on individual ovarian genes and their sequence-based data in the GenBank. The Ovarian Kaleidoscope database (OKdb) has accumulated nearly one thousand individual gene pages that are searchable based on gene function, cellular localization, chromosomal position, ovarian cell type, ovarian function, mutant phenotypes, and other criteria. The present review exemplifies the use of this organ-based database in setting up gene pathway maps for DNA array analysis, identifying key gene networks essential for infertility phenotypes, comparing chromosomal synteny regions for finding candidate fertility genes, categorizing cell-specific and hormonally coregulated genes for promoter analysis, and documenting potential ligands and receptors in the paracrine regulation of follicular development. The present global analysis of gene function and relationships in an organ-specific manner provides a functional genomic paradigm for the future understanding of the physiology and pathophysiology of diverse organs.

Animals↗

PubMed1993

Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression.

The cytochrome P450 steroid hydroxylases are coordinately regulated by steroidogenic factor 1 (SF-1), a protein expressed selectively in steroidogenic cells. Based on its expression in steroidogenic tissues and DNA-binding specificity, we isolated a putative SF-1 cDNA from an adrenocortical cDNA library. As evidence that this cDNA encodes SF-1, we now show that it is selectively expressed in steroidogenic cells, that an antiserum against its protein product specifically abolishes the SF-1-related gel-shift complex, and that its coexpression increases promoter activity of the 21-hydroxylase 5'-flanking region in transfection experiments. Sequence analyses of the SF-1 cDNA revealed that it is the mouse homolog of fushi tarazu factor I (FTZ-F1), a nuclear receptor that regulates the fushi tarazu homeobox gene in Drosophila. A second FTZ-F1 homolog, embryonal long terminal repeat-binding protein (ELP), was recently isolated from embryonal carcinoma cells. SF-1 and ELP cDNAs are virtually identical for 1017 base pairs, including putative DNA-binding domains, but diverge at their 5'- and 3'-ends. One genomic clone contained both SF-1- and ELP-specific sequences, confirming their origin from a single gene. Characterization of this gene defined shared exons encoding common regions and alternative promoters and 3'-exons leading to differences between the two FTZ-F1 transcripts. We used in situ hybridization with transcript-specific probes to study the ontogeny of SF-1 and ELP expression. ELP transcripts were not detected from embryonic day 8 to adult, consistent with its previous isolation from embryonal carcinoma cells and its postulated role in early embryonic development.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Neoplasms↗

PubMed2002

Mammalian resistance to oxidative stress: a comparative analysis.

Changes in gene expression represent a major protective mechanism, and enforced overexpression of individual genes has been shown to protect cells. However, no large-scale comparison of genes involved in mammalian oxidative stress protection has yet been described. Using filter microarray and restriction fragment differential display technology, hydrogen peroxide (H2O2)-resistant variants of hamster HA-1 fibroblasts and human HL-60 promyelocytes were found to possess a surprising lack of commonality in specific modulated genes with the single exception of catalase, supporting the hypothesis that catalase overexpression is critical for resistance to H2O2. Comparison of two cell lines from the same species (hamster) selected with an exogenous oxidative stressing agent (H2O2) and an endogenous metabolic oxidative stressing agent (95% O2) also revealed little commonality in modulation of specific mRNAs with the exception of glutathione S-transferase enzymes and catalase. Acute oxidative stress in HL-60 led to the modulation of a limited subset of the genes associated with chronic oxidative stress resistance. Overall, these results suggest that mammalian resistance to oxidative and perhaps other stress does not require a significant number of common genes but rather only a limited number of key genes (e.g., catalase in our model systems) in combination with others that are cell type and stress agent specific.

Animals↗

PubMed2025

Comprehensive circRNA expression profile and hub genes screening during human liver development.

BACKGROUND: Understanding the expression of non-coding RNA in the liver during embryonic development provides important insights into liver diseases. Therefore, we investigated circular RNA (circRNA) roles in human liver development, an unexplored research domain. METHODS: Using high-throughput sequencing and bioinformatics, we analysed foetal liver samples across developmental stages (7-20 weeks post-conception). Differentially expressed (DE) genes were identified and subjected to enrichment analysis using Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG), and Disease Ontology (DO). Modular analysis was performed using the Search Tool for Retrieval of Interacting Genes (STRING), followed by construction of a protein-protein interaction (PPI) network using Cytoscape software. The key genes were screened using Molecular Complex Detection (MCODE). The mRNA levels of hub genes were validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: There were 645 DE circRNAs and 5,145 DE mRNAs between human livers at the three growth stages (HB, EH, and LH). It was found that the activity of circRNAs was boosted remarkably in the hepatoblastic stage. Enrichment analysis found they mainly involved in nervous system regulation of liver function, embryonic organ development and digestive system development. In addition, DE circRNAs were primarily involved in the PI3K-AKT, MAPK and calcium pathways, potentially contributing to adult liver diseases. Notably, only hsa_circ_001471 and novel_circ_017382 were simultaneously identified at all stages and were persistently downregulated. A co-expression regulatory network involving these circRNAs was established. Three hub genes (LGR5, FOXL1 and RSPO3) were identified from the PPI network of 167 genes and may play key roles in human liver development. The RT-qPCR validation results were in agreement with the sequencing data. CONCLUSIONS: Our findings provide the first insights into the roles and regulatory networks of circRNAs in human liver development, laying the groundwork for further investigations of molecular and signalling networks.

Humans↗

PubMed2003

[Towards the positional cloning of a spikelet identity gene frizzle panicle (FZP) in rice (Oryza sativa L.)].

FZP is a key gene for spikelet differentiation in rice. Mutation of the gene blocks the differentiation of spikelets and makes rachis branches develop unlimitedly. A mutant of the gene named frizzle panicle (fzp) was previously found from the high-generation progeny of a cross between two Oryza sativa ssp. indica rice varieties, V20B and Hua1B. With the mutant, FZP had been mapped to a chromosomal region of about 26.4 cM in width between two SSR (Simple Sequence Repeat) markers, RM172 and RM18, on chromosome 7. In this study, high-resolution mapping of the gene was carried out for the positional cloning of the gene. Two flanking SSR markers, NRM6 and NRM8, were identified, which are 0.2 cM and 1.0 cM apart from the target gene, respectively, bracketing the target gene within an interval of 1.2 cM or 144 kb. An APETALA2 (AP2)-domain like gene was found at the expected position of FZP. As AP2 is known to play an important role in the floral development, we took it as the most possible candidate of FZP. PCR analysis showed that the mutant allele of the AP2-domain like gene contains an insert of about 4 kb in length, suggesting that the gene is very likely FZP.

Chromosome Mapping↗

PubMed2006

Aberrant promoter hypermethylation profile of cell cycle regulatory genes in malignant astrocytomas.

Aberrant hypermethylation of the CpG islands in the promoter region plays a casual role in the inactivation of various key genes involved in the cell cycle regulatory cascade, which could result in loss of cell cycle control. The aim of the present study was to investigate the role of promoter methylation of genes with a proven involvement in the cell cycle regulation of malignant astrocytomas. We profiled the CpG island methylation status of the RB1, p14ARF, p15INK4b, p16INK4a, p21Waf1/Cip1, p27Kip1, and p73 genes by methylation-specific polymerase chain reaction assay in a homogeneous cohort of patients with malignant astrocytomas, and assessed their relationships with clinical behavior. Promoter hypermethylation of the RB1, p14ARF, p15INK4b, p16INK4a, p21Waf1/Cip1, p27Kip1, and p73 genes was detected in 3 (6%), 7 (13%), 4 (7%), 2 (4%), 1 (2%), 3 (6%), and 12 samples (22%) among 54 newly diagnosed malignant astrocytomas, respectively. A total of 50% of the cases carried methylation of at least one gene, and only 9% of the cases displayed concordant hypermethylation of two genes. None of the tumors disclosed three or more methylated loci. The presence of methylation of these genes or a group of genes was not associated with any distinct clinicopathological characteristics including tumor grade, proliferation activity, responsiveness to adjuvant therapy, or patient survival. p73 protein accumulation was demonstrated by immunohistochemical staining in 6 (15%) of the 40 samples examined, with no significant association with the methylation status of p73 and any of the clinicopathological parameters tested. Our results demonstrated that a significant fraction of malignant astrocytomas displayed at least one methylated locus of the key cell cycle-related genes, although the genes were rarely hypermethylated, independent of the clinicopathological parameters. Thus, this epigenetic change is unlikely to play an important role in the evolution and development of malignant astrocytomas.

Adult↗

PubMed2003

Transcription profiling in rat liver in response to dietary docosahexaenoic acid implicates stearoyl-coenzyme a desaturase as a nutritional target for lipid lowering.

The gene expression profile in response to dietary docosahexaenoic acid rich oil for 6 wk was analyzed in the livers of male Sprague-Dawley rats to identify genes whose expression was regulated by dietary modification and correlated with serum lipid changes. Such genes may represent targets for intervention into cardiovascular health using nutraceuticals. High density glass microarrays containing approximately 7800 cloned expressed sequences from rat were used to identify those genes that responded to dietary long chain (n-3) fatty acids. In general, dietary long chain (n-3) fatty acids exhibited statistically significant lipid-lowering effects similar to a pharmaceutical alternative, fenofibrate, but showed narrower effects on the transcription of most of the genes assayed. The transcription patterns confirmed that the expression of several key genes involved in cholesterol metabolism, fatty acid beta-oxidation and lipogenesis was affected. These analyses indicated that stearoyl-coenzyme A (Delta9) desaturase, a key enzyme involved in the regulation of triglyceride biosynthesis and secretion, is a potential target for nutritional intervention for hyperlipidemia and cardiovascular health. In addition these results suggested that regulation of the farnesoid X receptor may be a key nutritionally regulated mediator of serum lipid changes. A nutritional product concept based on a convenient dietary aid demonstrated comparable efficacy with less spurious gene regulation than a pharmaceutical alternative.

Animals↗

PubMed2006

Pinoresinol-lariciresinol reductase gene expression and secoisolariciresinol diglucoside accumulation in developing flax (Linum usitatissimum) seeds.

The transcription activity of the pinoresinol-lariciresinol reductase (PLR) gene of Linum usitatissimum (so-called LuPLR), a key gene in lignan synthesis, was studied by RT-PCR and promoter-reporter transgenesis. The promoter was found to drive transcription of a GUSint reporter gene in the seed coats during the flax seed development. This fitted well with the tissue localization monitored by semi-quantitative RT-PCR of LuPLR expression. Accumulation of the main flax lignan secoisolariciresinol diglucoside was coherent with LuPLR expression during seed development. This three-way approach demonstrated that the LuPLR gene is expressed in the seed coat of flax seeds, and that the synthesis of PLR enzyme occurs where flax main lignan is found stored in mature seeds, confirming its involvement in SDG synthesis.

Base Sequence↗

PubMed2006

Molecular pathological analysis for determining the possible mechanism of piperonyl butoxide-induced hepatocarcinogenesis in mice.

Piperonyl butoxide (PBO), alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylene-dioxy-2-propyltoluene, is widely used as a synergist for pyrethrins. In order to clarify the possible mechanism of non-genotoxic hepatocarcinogenesis induced by PBO, molecular pathological analyses consisting of low-density microarray analysis and real-time reverse transcriptase (RT)-PCR were performed in male ICR mice fed a basal powdered diet containing 6000 or 0 ppm PBO for 1, 4, or 8 weeks. The animals were sacrificed at weeks 1, 4, and 8, and the livers were histopathologically examined and analyzed for gene expression using the microarray at weeks 1 and 4 followed by real-time RT-PCR at each time point. Reactive oxygen species (ROS) products were also measured using liver microsomes. At each time point, the hepatocytes of PBO-treated mice showed centrilobular hypertrophy and increased lipofuscin deposition in Schmorl staining. The ROS products were significantly increased in the liver microsomes of PBO-treated mice. In the microarray analysis, the expression of oxidative and metabolic stress-related genes--cytochrome P450 (Cyp) 1A1, Cyp2A5 (week 1 only), Cyp2B9, Cyp2B10, and NADPH-cytochrome P450 oxidoreductase (Por) was over-expressed in mice given PBO at weeks 1 and 4. Fluctuations of these genes were confirmed by real-time RT-PCR in PBO-treated mice at each time point. In additional real-time RT-PCR, the expression of Cyclin D1 gene, key regulator of cell-cycle progression, and Xrcc5 gene, DNA damage repair-related gene, was significantly increased at each time point and at week 8, respectively. These results suggest the possibility that PBO has the potential to generate ROS via the metabolic pathway and to induce oxidative stress, including oxidative DNA damage, resulting in the induction of hepatocellular tumors in mice.

Animals↗

PubMed2003

WAP1, a wheat APETALA1 homolog, plays a central role in the phase transition from vegetative to reproductive growth.

Heading time in bread wheat (Triticum aestivum L.) is determined by three characters: vernalization requirement, photoperiodic sensitivity and narrow-sense earliness, which are involved in the phase transition from vegetative to reproductive growth. We identified and characterized the APETALA1 (AP1)-like MADS box gene in wheat (WAP1) as an activator of phase transition. Its expression starts just before the phase transition and is maintained during the reproductive phase. Inhibition of WAP1 expression in the transgenic plants by co-suppression affected neither vernalization requirement nor photoperiodic sensitivity, but resulted in delayed narrow-sense earliness, indicating that WAP1 accelerates autonomous phase transition. Analyses of the WAP1 expression in the near-isogenic lines (NILs) for spring habit genes (Vrn) revealed that WAP1 transcripts were induced by vernalization strongly in the NILs with Vrn dominant alleles and weakly with the recessive alleles. Furthermore, WAP1 expression was up-regulated by a long photoperiod in both NILs with and those without a photoperiod-insensitive gene (Ppd). These results suggest that WAP1 is a key gene in the regulatory pathway controlling the phase transition from vegetative to reproductive growth in wheat.

Amino Acid Sequence↗

PubMed2006

Expression profiling of heat stress effects on mice fed ergot alkaloids.

Fescue toxicosis affects wild and domestic animals consuming ergot alkaloids contained in tall fescue forage infected with the endophytic fungus, Neotyphodium coenophialum. When animals are consuming infected fescue (E+) forage during periods of elevated ambient temperatures (summer), a range of phenotypic disorders collectively called summer slump is observed. It is characterized by hyperthermia, with an accompanying decrease in feed intake, growth, milk yield, and reproductive fitness. Laboratory mice also exhibit symptoms of fescue toxicosis at thermoneutral (TN) temperature, as indicated by reduced growth rate and reproductive fitness. Our goal was to characterize the differences in gene expression in liver of mice exposed to summer-type heat stress (HS) and E+ when compared to mice fed E+ at TN temperature. Mice were fed E+ diet under HS (34 +/- 1 degrees C; n = 13; E+HS) or TN conditions (24 +/- 1 degrees C; n = 14; E+TN) for a period of 2 weeks between 47 and 60 days of age. Genes differentially expressed between E+HS versus E+TN were identified using DNA microarrays. Forty-one genes were differentially expressed between treatment groups. Expressions of eight genes were measured using quantitative real-time PCR. Genes coding for phase I detoxification enzymes were upregulated in E+HS mouse liver. This detoxification pathway is known to produce reactive oxidative species. We observed an upregulation of genes involved in the protection against reactive oxidative species. Key genes involved in de novo lipogenesis and lipid transport were also upregulated. Finally, genes involved in DNA damage control and unfolded protein responses were downregulated.

Animal Feed↗

PubMed1997

Estrogen and progesterone receptors in the endometrium.

The endometrium, as a target of estrogens and progestins, possesses the respective receptor proteins. These receptors belong to the superfamily of nuclear receptors, having important functional domains required for steroid ligand binding, for dimer formation, for interaction with HREs of DNA, for transcription modulation, for association with other proteins, for intracellular trafficking, and other activities. The mechanism of action of the steroid hormones involves modulation of gene activity through interaction of the hormone-receptor complex with HREs and with other nuclear proteins, but also encompasses nongenomic effects, which accounts for the rapid effects of the steroids on cellular functions. Antihormones-antiestrogen and antiprogestins-compete with their respective hormones for binding sites on the receptor molecules. Some antihormones are partial agonists. The molecular mechanisms underlying the dual behavior of antihormones is under consideration. The concentration of ER and PR in different physiological and pathophysiological states, such as the menstrual cycle, pregnancy, and endometrial cancer, has been determined by biochemical and immuno(cyto)chemical methods. The levels of estrogens and progestins are important regulators of ER and PR gene expression. Estradiol acts as a cell mitogen, inducing key genes involved in replication, and its tumor promoter effect is discussed in this sense, whereas progesterone has reverse effects when compared to estradiol and acts as a differentiation factor. The cross-talk between the endocrine system, growth factors, and neurotransmitters can take place both at the receptor level, involving mainly phosphorylation reactions, and at the gene level, mainly through protein-protein interactions.

Endometrium↗

PubMed2006

Stress by heat shock induces massive down regulation of genes and allows differential allelic expression of the Gal/GalNAc lectin in Entamoeba histolytica.

Gene expression analysis by microarray assay revealed that when exposed to stress, Entamoeba histolytica exhibits a specific heat shock response, together with a dramatic overall reduction in gene transcription as well as differential allelic expression of key genes participating in virulence, such as the galactose/N-acetylgalactosamine (Gal/GalNAc) lectin.

Alleles↗

PubMed2001

General suppression of macrophage gene expression during Leishmania donovani infection.

Within the mammalian host, Leishmania donovani is an obligatory intracellular protozoan that resides and multiplies exclusively in the phagolysosomes of macrophages. The outcome of this infection is governed by the interaction between Leishmania and macrophage molecules that ultimately effect the expression of genes within both cells. To explore the effect of this intracellular infection on macrophage gene expression, a cDNA expression array analysis was performed to compare gene expression profiles in noninfected and L. donovani-infected macrophages. In this manner, it was possible to examine the effect of infection on the expression of several hundred well-characterized host cell genes in an unbiased manner. Interestingly, approximately 40% of the genes whose expression was detected in macrophages were down-regulated during infection with L. donovani. However, several genes were also induced during the infection process, some of which could play a role in recruitment of additional macrophages to the site of infection. Taken together, the general suppression of gene expression in addition to the selective induction of key genes is likely to play an important role in allowing the parasite to survive and proliferate within its host macrophage cell.

Animals↗

PubMed2006

Cell cycle, differentiation and regeneration: where to begin?

Hair cells, the sensory cells of inner ear, perform essential functions in hearing and balance. However, mammalian hair cells, like most of the CNS neurons, lack the capacity to regenerate. This is in sharp contrast to lower vertebrates in which hair cell regeneration occurs spontaneously through cell division of supporting cells, which leads to hearing restoration. It is believed that the lack of regeneration in mammals is, to a large degree, due to the block of cell cycle reentry imposed by negative cell growth genes in the inner ear. Recent studies have identified retinoblastoma gene, a well-known tumor suppressor, as the key gene involved in cell cycle exit of inner ear sensory cells. In the inner ear of pRb conditional knockout mice, hair cells undergo continuous cell division, and at the same time differentiate and become functional. Cell division continues in early postnatal cochlea and adult vestibule. Remarkably, the vestibular hair cells without pRb survive, and function at both the cellular and system levels. The time course and effects of pRb inhibition shows that there is a separation between the roles of pRb in cell cycle exit, and subsequent maturation and apoptosis. Those studies reveal distinctly different roles of pRb in the cochlear and vestibular sensory epithelia. The review discusses additional areas to be studied for regeneration of mature hair cells, and highlights the importance of transient and reversible block of pRb function as one of the routes to be explored for regeneration.

Animals↗

PubMed1999

Developmental genetics of the Drosophila gut: specification of primordia, subdivision and overt-differentiation.

The Drosophila gut is composed of three major parts, the foregut, midgut and hindgut, which arise from anterior and posterior invaginations of the early blastoderm. We review the process of the specification of the gut primordia, subsequent subdivision and region-specific cell differentiation in terms of developmental genetics. Graded activities of maternal signals at anterior and posterior terminal domains of the blastoderm, being mediated by activities of two zygotic gap genes, tailless and huckebein, lead to the activation of key genes that determine the gut primordia: serpent (GATA factor gene) for the endodermal midgut; brachyenteron (Brachyury homolog) for the ectodermal hindgut. fork head (HNF-3 homolog) and caudal (Cdx homolog) are also essential for the development of all gut primordia or hindgut primordium, respectively. Subdivision of the midgut epithelium is regulated by inductive signals emanating from the visceral mesoderm, which is under the control of HOM-C genes. In contrast, pattern formation of the ectodermal foregut and hindgut is regulated by secreted signaling molecules, such as Wingless (Wnt homolog), Hedgehog and Decapentaplegic (Bmp-4 homolog), as in the case of segmented structures and imaginal discs. Finally, the gut is subdivided into at least 36 compartments that are recognized asminimum tissue units of regional differentiation. A few genes that are responsible for determining and maintaining the state of overt-differentiation of the compartments have also been reported. A marked feature of the genetic mechanism of the gut development is the unexpectedly wide spectrum of the similarities of relevant genes and regulatory pathways of gene expression between Drosophila and vertebrates, which may imply a prototypic style of body plan common to protostomes and deuterostomes.

Animals↗