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PubMed2004

A gene atlas of the mouse and human protein-encoding transcriptomes.

The tissue-specific pattern of mRNA expression can indicate important clues about gene function. High-density oligonucleotide arrays offer the opportunity to examine patterns of gene expression on a genome scale. Toward this end, we have designed custom arrays that interrogate the expression of the vast majority of protein-encoding human and mouse genes and have used them to profile a panel of 79 human and 61 mouse tissues. The resulting data set provides the expression patterns for thousands of predicted genes, as well as known and poorly characterized genes, from mice and humans. We have explored this data set for global trends in gene expression, evaluated commonly used lines of evidence in gene prediction methodologies, and investigated patterns indicative of chromosomal organization of transcription. We describe hundreds of regions of correlated transcription and show that some are subject to both tissue and parental allele-specific expression, suggesting a link between spatial expression and imprinting.

Animals↗

PubMed2026

Comparative Population Genomics of Relictual Caribbean Island Gossypium hirsutum.

Gossypium hirsutum is the world's most important source of cotton fibre, yet the diversity and population structure of its wild forms remain largely unexplored. The complex domestication history of G. hirsutum combined with reciprocal introgression with a second domesticated species, G. barbadense, has generated a wealth of morphological forms and feral derivatives of both species and their interspecies recombinants, which collectively are scattered across a large geographic range in arid regions of the Caribbean basin. Here we assessed genetic diversity within and among populations from two Caribbean islands, Puerto Rico (n = 43, five sites) and Guadeloupe (n = 25, one site), which contain putative wild or introgressed forms. Using whole-genome resequencing data and a phylogenomic framework derived from a broader genomic survey, we parsed individuals into feral derivatives and truly wild forms. Feral cottons display uneven levels of genetic and morphological resemblance to domesticated cottons, with diverse patterns of genetic variation and heterozygosity. These patterns are inferred to reflect a complex history of interspecific and intraspecific gene flow that is spatially highly variable in its effects. Wild cottons in both Caribbean islands appear to be relatively inbred, especially the Guadeloupe samples. Our results highlight the dynamics of population demographics in relictual wild cottons that experienced profound genetic bottlenecks associated with repeated habitat destruction superimposed on a natural ecogeographical distribution comprising widely scattered populations. These results have implications for conservation and utilisation of wild diversity in G. hirsutum.

Genetics, Population↗

PubMed2005

Introduction to stroke genomics.

Translation of the explosion in knowledge of acute ischemic stroke into satisfactory treatment regimens has yet to happen. At present tPA, intra-arterial prourokinase and low-molecular-weight heparin form the vanguard for therapeutic intervention, yet these treatments have a limited therapeutic window. Part of this expansion in understanding has been driven by the contribution of stroke genetics and genomics. However, despite the enormous preclinical and clinical information of receptors, enzymes, second messenger systems, and so forth, that are implicated in stroke pathophysiology, delivery of novel drug treatment has been slow. This introductory chapter discusses the multiple sources of clinical and preclinical genetic information. It will describe the importance of integrating expression information into multiple preclinical models with temporal and spatial roles in lesion pathology and, furthermore developing an understanding of function in the clinic before claiming a role in ischemic stroke. The goal of such a holistic integration of information is to increase the yield from current datasets of gene expression and ultimately to help expand the choice of treatment available to the physician and patient.

Animals↗

PubMed2002

Rat MYH, a glycosylase for repair of oxidatively damaged DNA, has brain-specific isoforms that localize to neuronal mitochondria.

Mitochondrial genomes are exposed to a heavy load of reactive oxygen species (ROS) that damage DNA. Since in neurons, mitochondrial DNA integrity must be maintained over the entire mammalian life span, neuronal mitochondria most likely repair oxidatively damaged DNA. We show that the Escherichia coli MutY DNA glycosylase homolog (MYH) in rat (rMYH) involved in repair of oxidative damage is abundantly expressed in the rat brain, with isoforms that are exclusive to brain tissue. Confocal microscopy and western analyses reveal localization of rMYH in neuronal mitochondria. To assess involvement of MYH in the neuronal response to oxidative DNA damage, we used a rat model of respiratory hypoxia, in which acutely reduced blood oxygenation leads to generation of superoxide, and formation and subsequent removal of 8-hydroxy-2'-deoxyguanosine (8OHdG). Removal of 8OHdG is accompanied by a spatial increase in rMYH immunoreactivity in the brain and an increase in levels of one of the three mitochondrial MYH isoforms, suggesting that inducible and non-inducible MYH isoforms exist in the brain. The mitochondrial localization of oxidative DNA damage repair enzymes in neurons may represent a specialized neuronal mechanism that safeguards mitochondrial genomes in the face of routine and accidental exposures to heavy loads of injurious ROS.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2005

Location of Myc, Igh, and Igk on Robertsonian fusion chromosomes is inconsequential for Myc translocations and plasmacytoma development in mice, but Rb(6.15)-carrying tumors prefer Igk-Myc inversions over translocations.

The location of the Myc and immunoglobulin (Ig) loci on metacentric Robertsonian (Rb) fusion chromosomes may affect the development of mouse plasmacytomas (Pcts) by changing the probability with which chromosomal Myc-Ig translocations occur. To test this hypothesis, we induced Pcts in BALB/c (C) mice that carried Rb(4.12) and/or Rb(6.15) chromosomes. The Rb mice developed Pcts (n = 198) with similar onset and incidence to that in the inbred C mice. Karyotyping of 70 Rb-carrying Pcts demonstrated that in these tumors, just as in their counterparts in inbred C mice, the Igh heavy-chain locus was translocated with Myc more often than was the Igk light-chain locus. Pcts harboring Igh or Igk on normal and Rb chromosomes showed no bias toward either in generating Myc translocations. These findings indicated that the location of Myc, Igh, and Igk on normal or Rb chromosomes is inconsequential for Myc translocation and Pct development. In contrast, in Rb(6.15) mice, in which chromosomal inversions competed with chromosomal translocations for Igk-Myc juxtapositions, the former occurred more frequently than the latter in the resulting Pcts. This suggested that spatial proximity of Igk and Myc on the same chromosome facilitates the rearrangement of these loci. Myc translocation-dependent mouse Pct may provide a good model system for furthering our understanding of the relationship of higher-order genome organization in the interphase nucleus, origin of chromosomal translocations, and development of cancer.

Animals↗

PubMed2001

Intrinsic fluorescence from DNA can be enhanced by metallic particles.

High sensitivity detection of DNA is essential for genomics. The intrinsic fluorescence from DNA is very weak and almost all methods for detecting DNA rely on the use of extrinsic fluorescent probes. We show that the intrinsic emission from DNA can be enhanced many-fold by spatial proximity to silver island films. Silver islands are subwavelength size patches of metallic silver on an inert substrate. Time-resolved measurements show a decreased lifetime for the intrinsic DNA emission near the silver islands. These results of increased intensity and decreased lifetime indicate a metal-induced increase in the radiative rate decay of the DNA bases. The possibility of increased radiative decay rates for DNA bases and other fluorophores suggest a wide variety of DNA measurements and other biomedical assays based on metal-induced increases in the fluorescence quantum yield of weakly fluorescent substances.

Animals↗

PubMed1999

Limitations to tobacco mosaic virus infection of turnip.

Turnip vein-clearing virus (TVCV) and tobacco mosaic virus (TMV) represent subgroups of tobamoviruses infecting cruciferous and solanaceous plants, respectively. To identify adaptations that may have been necessary in the evolution of the TVCV subgroup from a TMV-like ancestor, the infection of turnip plants by TMV and by chimeras between TMV and TVCV was explored. TMV accumulated at spatially limited sites on inoculated turnip leaves as determined by leaf skeleton hybridization. A plasmid DNA containing a complete TVCV cDNA, when transcribed in vitro, produced RNA that was infectious to tobacco and turnip plants. TVCV-TMV chimeric genomes with junctions within coding regions were not infectious to tobacco, though the movement protein (MP) chimera was infectious to tobacco with a TMV MP transgene. Reciprocal chimeras with junctions between genes were infectious to tobacco. TVCV with a TMV MP gene infected turnips. The other tested chimeras were not detected in non-inoculated leaves, but were found in the inoculated leaves. Thus, the TMV MP is not responsible for the limitation of TMV spread in turnips.

Brassica↗

PubMed2005

Light activated recombination.

Many genes elicit their actions through their expression in precise spatial patterns in tissues. Photoregulated expression systems offer a means to remotely pattern gene expression in tissues. Using currently available photopatterning methods, gene expression is only transient. Herein is described a general method to permanently alter a cell's genome under the control of light. The photocaged estrogen receptor (ER) antagonists, nitroveratryl-hydroxytamoxifen (Nv-HTam) and nitroveratryl-hydroxytamoxifen aziridine (Nv-HTaz), mediate exposure-dependent recombination in cells expressing the Cre-ER, a fusion of the site-specific recombinase Cre and ER. Both Nv-HTam and Nv-HTaz only activate recombination by Cre-ER after exposure to light. When released only intracellularly, the covalent-modifying Taz can mediate significant amounts of recombination in an exposure-dependent manner. Nv-HTaz and Cre-ER represent perhaps the first compound that can be used to photopattern gene expression through recombination.

Cell Line↗

PubMed2005

Expression of the insulin receptor-related receptor is induced by the preovulatory surge of luteinizing hormone in thecal-interstitial cells of the rat ovary.

The insulin receptor-related receptor (IRR) is a member of the insulin receptor family that, on its own, recognizes neither insulin nor any of the identified insulin-related peptides. In both the nervous system and peripheral tissues, IRR mRNA is detected in cells that also express trkA, the nerve growth factor tyrosine kinase receptor. In the ovary, the trkA gene is transiently activated in thecal-interstitial cells of large antral follicles at the time of the preovulatory surge of gonadotropins. The present study shows that the IRR gene is expressed in the same ovarian compartment, that IRR mRNA content increases strikingly in these cells in the afternoon of the first proestrus, and that--as in the case of trkA mRNA--the increase is caused by gonadotropins. The IRR mRNA species primarily affected is that encoding the full-length receptor; its increased abundance was accompanied by a corresponding change in IRR protein content. An extensive molecular search using several approaches, including the screening of cDNA libraries and PCR amplification with degenerate primers, did not yield an IRR ligand. Phylogenetic analysis of 20 insulin-related sequences and 15 relaxin family peptides from selected vertebrates indicated that the mammalian genome is unlikely to contain an additional ligand expressed from a distinct gene that is closely related to the insulin family. Although the functional nature of the relationship between IRR and trkA receptors is unknown, the remarkable temporal and spatial specificities of their coordinated expression in the ovary before ovulation suggests that they target a functionally related set of downstream events associated with the ovulatory process.

Alternative Splicing↗

PubMed1990

Molecular action of the l(2)gl tumor suppressor gene of Drosophila melanogaster.

Tumor suppressor genes act as recessive determinants of cancer. These genes contribute to the normal phenotype and are required for regulating cell growth and differentiation during development. Inactivation of tumor suppressor genes leads to an unrestricted pattern of growth in specific cell types. In Drosophila, a series of genes have been identified that cause tissue-specific tumors after mutation. Of these, the lethal(2)giant larvae (l(2)gl) gene is the best studied. Homozygous l(2)gl mutations cause the development of malignant tumors in the brain and the imaginal discs. Genomic DNA from the l(2)gl locus has been cloned, introduced back into the genome of l(2)gl-deficient animals, and shown to reinstate normal development. The nucleotide sequence of the l(2)gl gene has been determined, as well as the sequences of two classes of transcripts. Analysis of the spatial distribution of both l(2)gl transcripts and proteins revealed that during early embryogenesis the l(2)gl gene is uniformly expressed in all cells and tissues. In late embryos, the l(2)gl expression becomes gradually restricted to tissues presenting no morphological or neoplastic alteration in the mutant animals. Further mosaic experiments revealed that l(2)gl gene loss can cause three distinct phenotypes: neoplastic transformation, abnormal differentiation, and normal development. These phenotypes depend upon the extent of gene activity in the stem cells prior to the formation of l(2)gl- clones. These analyses indicate that the critical period for the establishment of tumorigenesis occurs during early embryogenesis at a time when the l(2)gl expression is most intense in all cells.

Animals↗

PubMed2005

Molecular imaging: its application in cardiovascular diagnosis.

The emerging field of molecular and genomic imaging is providing new opportunities to visualize and quantify the biology of living organisms. To reach such goal all the major imaging modalities concur to this new field, each with its mechanism for generating contrast and with its spatial resolution and specificity. This review deals with a brief introduction to the molecular imaging principles and reports on the state-of-the-art in cardiovascular disease.

Animals↗

PubMed2026

Spatial transcriptomics of primary and metastatic ALK-rearranged NSCLC reveals site-specific adaptations.

INTRODUCTION: Genetic alterations and the tumor microenvironment (TME) influence treatment response in anaplastic lymphoma kinase-rearranged non-small cell lung cancer (ALK+ NSCLC). This study maps site-specific TME adaptations and exploratory risk-associated signatures in lymph node metastases (LNT) to investigate metastatic evolution. METHOD: We applied spatial transcriptomics to profile tumor (PanCK+) and stromal (PanCK-) compartments in a pilot cohort of 16 cases: primary lung tumors (LT, n = 3), LNT (n = 10), and brain metastases (BT, n = 3), with three site-matched non-tumor controls. LNT-derived prognostic signatures were evaluated using The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA LUAD) cohorts. RESULTS: Distinct, site-specific TME features were observed. LNT stroma was enriched in fibroblasts and macrophages, while tumor segments showed increased neutrophils. BT exhibited a macrophage-associated immunosuppressive TME. Tumor cells evolved divergently: LT retained pulmonary identity and showed trend towards translation-associated programs, LNT cells shifted toward senescence and epigenetic remodeling, and BT cells showed activation of Class A/1 (Rhodopsin-like) receptor, GPCR and drug metabolism pathways. In LNT, exploratory risk-associated differences were observed. Low-risk cases (n = 6) showed adaptive immune signatures, whereas high-risk cases (n = 4) showed enrichment for stromal MET signaling and stress-response pathways. Because treatment exposure differed markedly between the risk groups, these observations should be interpreted as hypothesis-generating. TCGA LUAD analysis suggested the broader biological relevance of immune-associated markers, but reflected general LUAD rather than ALK+ specific biology. Discordant associations for GCLC and TIMP1 underscored the importance of spatial context. CONCLUSION: Site-specific microenvironments may influence tumor adaptation across metastatic niches in ALK+ NSCLC. The exploratory risk-associated findings require validation in larger, uniformly treated cohorts.

Humans↗

PubMed1998

Muscle-specific locus control region activity associated with the human desmin gene.

We describe the reproduction of the full pattern of expression of the muscle-specific desmin gene in transgenic mice using a 240-kb genomic clone spanning the human desmin locus. Analysis of RNA from adult tissues demonstrated that this fragment possesses all the necessary genetic regulatory elements required to provide reproducible, site-of-integration-independent, physiological levels of tissue-specific expression that is directly proportional to transgene copy number in all muscle cell types. In situ hybridization revealed that in marked contrast to murine desmin which is strongly expressed in the myotome of the somites, skeletal muscles, the heart, and smooth muscle of the vasculature by 9.5 days postcoitum, human desmin transgene expression was completely absent from smooth muscles, was very weak and restricted to the atrium and outflow tract within the heart, and was expressed at only 5% of murine desmin mRNA levels within the myotome of the somites. The spatial distribution and levels of human and mouse desmin expression were not coincident until 14.5 days postcoitum. Immunohistochemical analysis of human embryos at comparable stages of development showed that this transgene faithfully reproduces the human and not the mouse developmental expression pattern for this gene in transgenic mice. These results indicate that the 240-kb desmin genomic clone is capable of establishing an independent, chromatin domain in transgenic mice and provides the first definitive data for muscle-specific locus control region activity. In addition, our results demonstrate that the behavior of human transgenes in mice should, whenever possible, be compared to expression patterns for that gene in human embryonic as well as adult tissues.

Animals↗

PubMed2006

Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice.

This objective of this study was to investigate the toxicogenomics and the spatial regulation of global gene expression profiles elicited by endoplasmic reticulum (ER) stress inducer tunicamycin (TM) in mouse small intestine and liver as well as to identify TM-modulated nuclear factor-E2-related factor 2 (Nrf2)-dependent genes. Gene expression profiles were analyzed using 45,000 Affymetrix mouse genome 430 2.0 array and GeneSpring 7.2 software. Microarray results were validated by quantitative real-time reverse transcription-PCR analyses. Clusters of genes that were either induced or suppressed more than two-fold by TM treatment compared with vehicle in C57BL/6J/Nrf2 (-/-; knockout) and C57BL/6J Nrf2 (+/+; wildtype) mice genotypes were identified. Amongst these, in small intestine and liver, 1291 and 750 genes, respectively, were identified as Nrf2-dependent and upregulated, and 1370 and 943 genes, respectively, as Nrf2-dependent and downregulated. Based on their biological functions, these genes can be categorized into molecular chaperones and heat shock proteins, ubiquitination/proteolysis, apoptosis/cell cycle, electron transport, detoxification, cell growth/differentiation, signaling molecules/interacting partners, kinases and phosphatases, transport, biosynthesis/metabolism, nuclear assembly and processing, and genes related to calcium and glucose homeostasis. Phase II detoxification/antioxidant genes as well as putative interacting partners of Nrf2 such as nuclear corepressors and coactivators, were also identified as Nrf2-dependent genes. The identification of TM-regulated and Nrf2-dependent genes in the unfolded protein response to ER stress not only provides potential novel insights into the gestalt biological effects of TM on the toxicogenomics and spatial regulation of global gene expression profiles in cancer pharmacology and toxicology, but also points to the pivotal role of Nrf2 in these biological processes.

Animals↗

PubMed2002

Thalamic neuron theory: meridians=DNA. The genetic and embryological basis of traditional Chinese medicine including acupuncture.

This hypothesis proposes a mechanism by which the genetic information contained in the one-dimensional genome may be converted into a three-dimensional body plan for development. Prior to mitosis of the fertilized egg, the chromatids, after being unpackaged from the chromosomes, link up to form a giant circular loop which is then folded upon itself into a wired-frame structure that embodies the architectural embryological developmental scheme. This intranuclear spatial body design is then translated into a three-dimensional cellar plan surrounding the fertilized egg with the positional value of each surrounding daughter cell preferentially activated by specific spatially oriented gene products diffused through the neatly arranged nuclear pores of the cell nucleus of the fertilized egg. This group of cells of the primitive embryo then leads to the formation of the Spemann Organizer, which directs embryological development of the brain as well as the rest of the body. The Spemann Organizer thus retains control over the CNS which in turn controls the development and functions of the peripheral tissues. The chains of cells that compose the Spemann Organizer, forming a homunculus in the image of the wired frame formed by the chromatids are believed to be the equivalents of acupuncture meridians. To support the hypothesis, evidence is also presented to substantiate the intimate relationships between the acupuncture meridians and embryological development, evolution, the central nervous system as well as the genome. This theoretical model is capable of dispelling the mystery of acupuncture, traditional Chinese medicine and myriads of modern clinical observations, and may have the potential to usher in a multitude of innovative therapeutic methods for many difficult to treat medical conditions.

Acupuncture↗

PubMed1996

Developmental pattern of expression and genomic organization of the calponin-h1 gene. A contractile smooth muscle cell marker.

Calponin-h1 is a 34-kDa myofibrillar thin filament, actin-binding protein that is expressed exclusively in smooth muscle cells (SMCs) in adult animals. To examine the molecular mechanisms that regulate SMC-specific gene expression, we have examined the temporal, spatial, and cell cycle-regulated patterns of expression of calponin-h1 gene expression and isolated and structurally characterized the murine calponin-h1 gene. Calponin-h1 mRNA is expressed exclusively in SMC-containing tissues in adult animals. During murine embryonic development, calponin-h1 gene expression is (i) detectable in E9.5 embryos in the dorsal aorta, cardiac outflow tract, and tubular heart, (ii) sequentially up-regulated in SMC-containing tissues, and (iii) down-regulated to non-detectable levels in the heart during late fetal development. In addition, the gene is expressed in resting rat aortic SMCs, but its expression is rapidly down-regulated when growth-arrested cells reenter phase G1 of the cell cycle and proliferate. Calponin-h1 is encoded by a 10.7-kilobase single copy gene composed of seven exons, which is part of a multigene family. Transient transfection analyses demonstrated that 1.5 kilobases of calponin-h1 5'-flanking sequence is sufficient to program high level transcription of a luciferase reporter gene in cultured primary rat aortic SMCs and the smooth muscle cell line, A7r5. Taken together, these data suggest that the calponin-h1 gene will serve as an excellent model system with which to examine the molecular mechanisms that regulate SMC lineage specification, differentiation, and phenotypic modulation.

Amino Acid Sequence↗

PubMed1992

Bracteomania, an inflorescence anomaly, is caused by the loss of function of the MADS-box gene squamosa in Antirrhinum majus.

Anomalous flowering of the Antirrhinum majus mutant squamosa (squa) is characterized by excessive formation of bracts and the production of relatively few and often malformed or incomplete flowers. To study the function of squamosa in the commitment of an inflorescence lateral meristem to floral development, the gene was cloned and its genomic structure, a well as that of four mutant alleles, was determined. SQUA is a member of a family of transcription factors which contain the MADS-box, a conserved DNA binding domain. In addition, we analysed the temporal and spatial expression pattern of the squa gene. Low transcriptional activity of squa is detectable in bracts and in the leaves immediately below the inflorescence. High squa transcript levels are seen in the inflorescence lateral meristems as soon as they are formed in the axils of bracts. Squa transcriptional activity persists through later stages of floral morphogenesis, with the exception of stamen differentiation. Although necessary for shaping a normal racemose inflorescence, the squa function is not absolutely essential for flower development. We discuss the function of the gene during flowering, its likely functional redundancy and its possible interaction with other genes participating in the genetic control of flower formation in Antirrhinum.

Alleles↗

PubMed1999

High resolution FISH in plants - techniques and applications.

Fluorescence in situ hybridization (FISH) is an effective and accurate cytogenetic tool for mapping single copy and repetitive DNA sequences on chromosomes. Attempts to increase the detection sensitivity of very small chromosomal targets, and to improve the spatial resolution of signals derived from flanking sequences, have led to the development of a variety of novel techniques: it is now possible to perform in situ hybridizations on interphase nuclei, meiotic pachytene chromosomes and isolated chromatin (DNA fibres). The recent application of these techniques has indicated that a spatial resolution of 1 kb between adjacent targets and a sensitivity of targets smaller than 1 kb is now feasible. Here, we describe the benefits of these novel chromosome analysis techniques and discuss their relevance for the study of plant genomes.

Journal Article↗