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Site-specific recombination systems are powerful tools for introducing predetermined modifications into eukaryotic genomes. Recent advances allow the manipulation of chromosomal DNA in a spatially and temporally controlled manner in mice, offering unprecedented possibilities for studying mammalian genome function and for generating animal models for human diseases.
Histone acetylation, a reversible modification of the core histones, is widely accepted to be involved in remodeling chromatin organization for genetic reprogramming. Histone acetylation is a dynamic process that is regulated by two classes of enzymes, the histone acetyltransferases (HATs) and histone deacetylases (HDACs). Although promoter-specific acetylation and deacetylation has received most of the recent attention, it is superimposed upon a broader acting and dynamic acetylation that profoundly affects many nuclear processes. In this study, we monitored this broader histone acetylation as cells enter and exit mitosis. In contrast to the hypothesis that HATs and HDACs remain bound to mitotic chromosomes to provide an epigenetic imprint for postmitotic reactivation of the genome, we observed that HATs and HDACs are spatially reorganized and displaced from condensing chromosomes as cells progress through mitosis. During mitosis, HATs and HDACs are unable to acetylate or deacetylate chromatin in situ despite remaining fully catalytically active when isolated from mitotic cells and assayed in vitro. Our results demonstrate that HATs and HDACs do not stably bind to the genome to function as an epigenetic mechanism of selective postmitotic gene activation. Our results, however, do support a role for spatial organization of these enzymes within the cell nucleus and their relationship to euchromatin and heterochromatin postmitotically in the reactivation of the genome.
Olfactory transduction begins with the binding of an odorous molecule to a protein receptor--odorant receptor--on the cell surface of olfactory neuron. Odorant receptors are encoded by a large gene family belonging to the superfamily of G-protein-coupled, seven-transmembrane-domain receptors. Since the identification of the receptor gene family in 1991, a considerable amount of progress has been made in the study of odorant receptors, including aspects of spatial and temporal expression pattern, the genomic organization of the receptor genes, regulation of expression, and receptor function. These studies are of critical importance in understanding how the olfactory system recognizes and distinguishes thousands of odors.
Glucocorticoids have been the mainstay of anti-inflammatory therapy for the past 50 years despite the significant risks associated with their long-term use. Recent research into the molecular mechanisms of action of these compounds can be aggregated into two major themes: first, those that focus on the involvement of the glucocorticoid receptor in regulating the transcription of pro-inflammatory genes; and second, studies that seek to identify alternative pathways of glucocorticoid action either via the induction of anti-inflammatory mediators or through rapid non-genomic mechanisms. Understanding the temporal-spatial patterns of these multiple mechanisms on relevant cell types will be key to explaining the profound effects that these four-ring steroids exert on the inflammatory process.
Protein kinases are key participants in signal transduction pathways. A direct assessment of the relationship between the activity of any given protein kinase and the corresponding cellular phenotype has proven challenging. This is due to the large number of protein kinases encoded by the human genome coupled with intracellular temporal and spatial constraints that appear to further regulate the ultimate response of a cell to a stimulus. Our work has focused on the development of chemical probes to address the complexities associated with protein kinase-mediated cell signaling. These include the acquisition of highly selective substrates and inhibitors for specific members of the protein kinase family, the design and synthesis of light-activated signaling proteins and their corresponding inhibitors, and the preparation of fluorescent reporters of intracellular protein kinase action.
Accurate breast cancer subtyping guides treatment selection, yet histopathology captures morphology without molecular state, while genomic profiling captures molecular signatures without spatial context. Existing fusion methods rely on concatenation, or on attention applied only after each modality is encoded independently. This work identifies a scale-dependent asymmetry in the direction of cross-modal conditioning: the direction that performs best under limited samples is not the one that holds at scale, and the reversal is traced to the capacity of the modulation pathway rather than to the fusion principle. The comparison is carried out within a hypernetwork-guided framework in which an auxiliary network maps one modality to conditioning parameters that modulate the other's feature representation, shaping features at the parametric level rather than the decision stage; modulation is patient-specific rather than patch-specific. Both directions are instantiated-gene-to-image (HyperG2I) and image-to-gene (HyperI2G) - and trained under a label-aware MixUp strategy that interpolates within-class samples across both modalities, preserving the hard binary labels clinical decisions require. The framework is evaluated on two paired TCGA-BRCA cohorts-one limited-sample, one independently assembled at scale-under a single protocol spanning two whole-slide representations, multiple visual backbones, and both conditioning directions. On the limited-sample cohort, gene-to-image conditioning at its optimal augmentation setting exceeds early fusion and both unimodal baselines, giving the highest recall on the aggressive Basal/HER2 class of any configuration evaluated, and an ablation favours intra-class over inter-class mixing. At scale this ordering does not hold: image-to-gene conditioning sustains its performance whereas gene-to-image does not, recovering only partially under the full tissue bag and isolating the capacity of the modulation pathway as the binding constraint. Direction and capacity of cross-modal conditioning, rather than fusion depth alone, therefore govern how such frameworks scale.
Many empirical studies show that there are unusual clusters of palindromes, closely spaced direct and inverted repeats around the replication origins of herpesviruses. In this paper, we introduce two new scoring schemes to quantify the spatial abundance of palindromes in a genomic sequence. Based on these scoring schemes, a computational method to predict the locations of replication origins is developed. When our predictions are compared with 39 known or annotated replication origins in 19 herpesviruses, close to 80% of the replication origins are located within 2% of the genome length. A list of predicted locations of replication origins in all the known herpesviruses with complete genome sequences is reported.
During spermatogenesis, DNA in the sperm head becomes more tightly condensed as histones are replaced by protamine-like molecules. In this article, the question is asked whether, during the production of this highly differentiated cell, controls are imposed on the spatial organization of DNA within the nucleus. Heads from bull spermatozoa were isolated by a technique that removed the plasma membrane and acrosomal contents, and the DNA was induced to decondense by addition of 2-mercaptoethanol and trypsin. Under these conditions, decondensation was induced in all regions of the head. To determine whether there was any spatial restraint on packaging of the genome, three DNA probes were used (pl.709-512, containing an interspersed repetitive sequence; pCSIH, containing a copy of the major bovine centromeric statellite sequence; p18 s and p28 s, containing the 18 S and 28 S ribosomal genes) that might be expected to hybridize to different regions. Results showed that the interspersed repetitive probe hybridized to all regions of the head, whereas the ribosomal and centromeric probes hybridized to sequences that were largely confined to the equatorial region of the sperm. We conclude that organization of the genome in the bovine sperm nucleus is not random.
Neurogenomics is the study of how the genome as a whole contributes to the evolution, development, structure and function of the nervous system. It includes investigations of how genome products (transcriptomes and proteomes) vary in time and space. Neurogenomics differs markedly from the application of genome sciences to other systems, particularly in the spatial category, because anatomy and connectivity are paramount to our understanding of function in the nervous system. We focus here on some of the influences of genomics and its associated technologies on neuroscience. We discuss comparative genomics, gene expression atlases of the brain, network genetics and applications to behavioral phenotypes, and consider the culture, organization and funding of genome-scale projects.
Insulin-like growth factor II (Igf2) is maternally imprinted in normal tissues with only the paternal copy of the gene being transcribed, whereas the contiguous gene H19 is paternally imprinted. Dysregulation of IGF2 imprinting is commonly observed in Wilms' tumor and other human tumors. Previous work comparing promoter-specific imprinting of human and mouse Igf2 suggested the presence of a cis element upstream of Igf2 that regulates or maintains the imprinting of three downstream promoters. To explore the molecular mechanism of maintenance of genomic imprinting, we targeted the region between insulin 2 and Igf2, where the cis imprint maintenance element (IME) resides in mouse fibroblasts. In those clones in which the targeting vector was randomly integrated into the genome, mouse Igf2 remained imprinted. However, when the targeted region containing the IME was deleted by homologous recombination, whether from the paternal or maternal allele, activation of the imprinted maternal allele of Igf2 was observed. In addition, there was a loss of H19 imprinting when the IME was deleted. The requirement of IME from both parental alleles for the maintenance of genomic imprinting thus suggests the importance of a spatial structure of DNA around Igf2 and H19. Modifications in the IME, like abnormal methylation in Wilms' tumors, may represent a novel mechanism for loss of genomic imprinting.
Identification of temporal and spatial changes in myometrial gene expression during parturition may further the understanding of the coordinated regulation of myometrial contractions during parturition. The objective of this study was to compare the gene expression profiles of human fundal myometrium from pregnant women before and after the onset of labor using a functional genomics approach, and to further characterize the spatial and temporal expression patterns of three genes believed to be important in parturition. Fundal myometrial mRNA was isolated from five women in labor and five women not in labor, and analyzed using human UniGEM-V microarrays with 9182 cDNA elements. Real-time polymerase chain reaction using myometrial RNA from pregnant women in labor or not in labor was used to examine mRNA levels for three of the genes; namely, prostaglandin-endoperoxide synthase 2 (PTGS2), calgranulin B (S100A9), and oxytocin receptor (OXTR). The spatial expression pattern of these genes throughout the pregnant uterus before and after labor was also determined. Immunolocalization of cyclooxygenase-2 (also known as PTGS2) and S100A9 within the uterine cervix and myometrium were analyzed by immunohistochemistry. Few genes were differentially expressed in fundal myometrial tissues at term with the onset of labor. However, there appears to be a subset of genes important in the parturition cascade. The cellular properties of S100A9, its spatial localization, and dramatic increase in cervix and myometrium of women in labor suggest that this protein may be very important in the initiation or propagation of human labor.
High-grade gliomas (HGGs), particularly glioblastoma (GBM), remain among the most lethal human cancers despite decades of molecular profiling and therapeutic innovation. A primary reason for treatment failure is that HGG biology is spatial: malignant cell states, immune suppression, metabolic stress, and therapeutic resistance are organized into distinct anatomical and functional niches. Spatial omics technologies now enable high-dimensional mapping of gene expression, protein signaling, immune architecture, and metabolic activity within intact tumor tissue. These approaches reveal how proneural and mesenchymal transcriptional states coexist yet localize to distinct regions, alongside hypoxic, invasive, and stem-enriched niches. Spatial analyses show that key clinical determinants, including O6-methylguanine-DNA methyltransferase (MGMT)-associated temozolomide resistance, radiotherapy tolerance in hypoxic regions, and immunotherapy failure driven by myeloid-dominated immune exclusion, are influenced not only by molecular programs but also by cellular location. Beyond biological insight, spatial omics is reshaping clinical paradigms by enabling region-specific patient stratification, early assessment of treatment response, and identification of therapy-resistant reservoirs that seed recurrence. Prior bulk and single-cell studies defined HGG cell states and pathways but often treated resistance as tumor-wide. This review presents a spatially explicit framework that synthesizes spatial transcriptomic and immune-profiling studies to identify tumor-immune niches and spatial bottlenecks that drive therapeutic failure and recurrence.
Regulation of cellular growth implies spatiotemporally coordinated programmes of gene transcription. A central question, therefore, is how global transcription is coordinated in the genome. The growth of the unicellular organism Escherichia coli is associated with changes in both the global superhelicity modulated by cellular topoisomerase activity and the relative proportions of the abundant DNA-architectural chromatin proteins. Using a DNA-microarray-based approach that combines mutations in the genes of two important chromatin proteins with induced changes of DNA superhelicity, we demonstrate that genomic transcription is tightly associated with the spatial distribution of supercoiling sensitivity, which in turn depends on chromatin proteins. We further demonstrate that essential metabolic pathways involved in the maintenance of growth respond distinctly to changes of superhelicity. We infer that a homeostatic mechanism organizing the supercoiling sensitivity is coordinating the growth-phase-dependent transcription of the genome.
Linkage disequilibrium (LD) in the human genome, often measured as pairwise correlation between adjacent markers, shows substantial spatial heterogeneity. Congruent with these results, studies have found that certain regions of the genome have far less haplotype diversity than expected if the alleles at multiple markers were independent, while other sets of adjacent markers behave almost independently. Regions with limited haplotype diversity have been described as "blocked" or "haplotype blocks." In this article, we propose a new method that aims to distinguish between blocked and unblocked regions in the genome. Like some other approaches, the method analyses haplotype diversity. Unlike other methods, it allows for adjacent, distinct blocks and also multiple, independent single nucleotide polymorphisms (SNPs) separating blocks. Based on an approximate likelihood model and a parsimony criterion to penalize for model complexity, the method partitions a genomic region into blocks relatively quickly, and simulations suggest that its partitions are accurate. We also propose a new, efficient method to select SNPs for association analysis, namely tag SNPs. These methods compare favorably to similar blocking and tagging methods using simulations.
A complex study of the spatial arrangement of different genetic elements (genes, centromeres and chromosomal domains) in the cell nucleus is presented and the principles of this arrangement are discussed. We show that the radial location of genetic elements in the three-dimensional (3D) space between the center of the nucleus and the nuclear membrane is element specific and dependent on the position of the element on the chromosome. In contrast, mutual angular positioning of both homologous and heterologous genetic elements is, in the majority of cases, random. In several cases, tethering of heterologous genetic elements was observed. This close proximity of specific loci may be responsible for their mutual rearrangement and the development of cancer. Comparison of our results with transcriptome maps shows that the nuclear location of chromosomal domains with highly expressed genes is more central when compared with chromosomes with low expression. The higher-order chromatin structure is strikingly similar in various human cell types, which correlates with the fact that the profiles of gene expression are also similar.
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.
The genomic and cDNA sequences of the MSCP14.6 gene section, which encodes a Manduca sexta cuticle protein, have been determined. The genomic sequence presented here includes 1428 N of 5' flanking DNA, 1587 N of transcribed DNA, and 465 N of 3' flanking DNA. The intron/exon boundaries mapped by comparison of these sequences were confirmed by primer extension and SI nuclease mapping. Prior work showed that the RNA produced by this gene is regulated both temporally and spatially during larval, pupal, and adult development, and also showed that both 20-hydroxyecdysone (20E) and juvenile hormone (JH) are important in controlling the amount of RNA present in the epidermis (Riddiford et al., 1986). In situ hybridizations show that MSCP14.6 is expressed throughout the epidermis in larvae and is spatially restricted in pharate pupal and pharate adult stages. The results presented here delimiting the transcription unit and 5' flanking DNA of the MSCP14.6 gene will facilitate further research to determine the DNA elements necessary for regulation of gene expression.
Genome stability is crucial for the complete maintenance of the cellular pathways that govern the cell cycle. As a result of irregularities in DNA replication occurring throughout the S phase, key genes that regulate cell cycle pathways are damaged, giving rise to single-base mutations and chromosomal aberrations. Thus, the efficient replication of the genome, which depends on a precise temporal and spatial pattern of activation of origins of replication, is greatly impaired. The approach discussed below aims at monitoring the replication pattern and the kinetics of replication throughout the entire genome of living cells. It could shed light on the mechanisms by which drugs act on DNA replication and, moreover, it might assist the discovery and design of novel drugs that inhibit cell proliferation under pathophysiological conditions.