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PubMed1992

Recent advances in fluorescence in situ hybridization.

Fluorescence in situ hybridization (FISH) procedures that directly couple molecular and cytological information allow precise visualization of DNA sequences on metaphase chromosomes and interphase nuclei. These techniques can be used to identify chromosomes, detect chromosomal aberrations, and analyze linear and spatial genome organization. FISH procedures are also used to clinical fields for diagnosis of disease-related chromosome changes and tumor biology.

Animals↗
PubMed2026

Spatially ordered zygotic genome activation fulfills embryo quality control.

Early embryo development features autonomous, maternally driven cell divisions that self-organize the multicellular blastula or blastocyst tissue. Maternal control cedes to the zygote starting with the onset of widespread zygotic genome activation (ZGA), which is essential for subsequent cell fate determination and morphogenesis. Intriguingly, although ZGA onset is highly regulated at the level of the whole embryo, it can be non-homogenous and precisely patterned at the single-cell level. We previously demonstrated a stereotyped spatial and temporal ordering of ZGA in a model vertebrate embryo. Unknown, however, was whether this precise ZGA patterning was required for development. To address this fundamental question, we devised a strategy to spatially control cell divisions that perturb blastula embryo organization. We demonstrate the feasibility of spatially inverting the cell size pattern of embryos and find that these inverted embryos exhibit a flipped pattern of ZGA. Mispatterned ZGA along the animal-vegetal axis triggers embryo apoptosis, revealing that gastrula embryos have a built-in quality control system to sense inappropriate ZGA patterning, including regionalized defects in transcriptional onset. The quality control response is nonautonomous, dependent on an anti-apoptotic signal that suppresses cell death outside the animal hemisphere. These results reveal the requirement of properly patterned ZGA for normal development and the existence of a surveillance system of embryo quality control exquisitely tuned to the spatial and temporal ordering of genome activation and zygotic gene expression.

Animals↗
PubMed2025

Spatially ordered zygotic genome activation fulfills embryo quality control.

Early embryo development features autonomous, maternally-driven cell divisions that self- organize the multicellular blastula or blastocyst tissue. Maternal control cedes to the zygote starting with the onset of widespread zygotic genome activation (ZGA), which is essential for subsequent cell fate determination and morphogenesis. Intriguingly, although the onset of ZGA is highly regulated at the level of an embryo, it can be non-homogenous and precisely patterned at the single-cell level. We previously demonstrated a stereotyped spatial and temporal ordering of ZGA in a model vertebrate embryo. Unknown, however, was whether this precise ZGA patterning was required for development. To address this fundamental question, we devised a strategy to spatially control cell divisions in the embryo that perturb blastula embryo organization. We demonstrate the feasibility of spatially inverting the cell size pattern of embryos and find that these inverted embryos undergo a flipped pattern of ZGA. Mispatterned ZGA along the animal-vegetal axis causes embryo apoptosis, revealing that gastrula embryos have a built-in quality control system to sense inappropriate ZGA patterning, including regional defects in transcriptional onset. The quality control response is non-autonomous which may depend on anti-apoptotic signals that repress cell death outside of the animal hemisphere. These results reveal the requirement of properly patterned ZGA for normal development and the existence of an embryo quality control response exquisitely tuned to the spatial and temporal ordering of genome activation and zygotic gene expression.

Journal Article↗
PubMed2004

Characterization of mouse orthologue of ELOVL4: genomic organization and spatial and temporal expression.

Mutations in ELOVL4 are associated with dominant macular degeneration (adMD/STGD3). This gene is highly expressed in the retina and is conserved through evolution. Here we report the genomic organization of the mouse orthologue of ELOVL4 and its temporal and spatial expression. A significant amount of ELOVL4 mRNA expression is detected in the adult retina, brain, skin, testis, and lens. During development, expression is first noted at embryonic day 7 (E7). A significant level of the mRNA is observed both in brain and in eyes at postnatal day 1 (P1), after which levels decrease in the brain and increase in the retina until they stabilize at P30. ELOVL4 protein is evident in the ocular tissues by E10.5 and becomes restricted predominantly to the photoreceptor layer in the mature retina. These observations suggest that ELOVL4 may play an important role in embryonic development and in maintaining normal physiology of retina and brain at later stages of development.

Animals↗
PubMed2026

Spatially Contextualized Integrative Genomics Highlights Neuronal and Glial Regulatory Programs in Low Back Pain.

PURPOSE: Low back pain (LBP) is a heterogeneous pain condition with a measurable genetic contribution, but the genes, brain cell types, and spatial tissue contexts through which inherited risk is expressed remain unclear. We aimed to define cell-type-specific and spatially contextualized genetic mechanisms underlying LBP. METHODS: FinnGen R12 LBP GWAS summary statistics (42,521 cases and 353,224 controls) were integrated with brain single-nuclei eQTL data across eight major brain cell classes. We evaluated genome-wide polygenic signal using LDSC, prioritized genes using MAGMA and PoPS, and performed brain cell-type-specific eQTL-anchored Mendelian randomization, primarily based on single-instrument Wald ratio estimates, followed by Bayesian colocalization. Spatial genetic mapping was conducted using gsMap in an E16.5 murine embryonic atlas and two adult human lumbar spinal cord Visium sections. Selected candidates were assessed by RT-qPCR in neuronal-like and astroglial-like inflammatory cell models. RESULTS: LDSC supported interpretable polygenic signal for LBP. MAGMA and PoPS showed partial gene-level convergence, with TCF4 and TMEFF2 supported by both approaches. Across 1641 tested gene-cell type exposures, significant eQTL-anchored MR associations were concentrated in excitatory neurons, oligodendrocytes, inhibitory neurons, and astrocytes. Integrated eQTL-anchored MR, colocalization, and gene-prioritization evidence highlighted CLEC18A, QPRT, and GMPPB as higher-priority non-MHC candidates with moderate, but not strong, colocalization support. gsMap localized LBP-associated enrichment to neuroaxis-related embryonic regions, including brain, spinal cord, sympathetic nerve, and dorsal root ganglion, and to neuronal-like niches in adult lumbar spinal cord. RT-qPCR showed model-dependent expression changes, with QPRT and LGI4 preferentially responsive in neuronal-like SH-SY5Y cells and GMPPB and DPYSL5 responsive in astroglial-like U251 cells. CONCLUSION: These findings support neuronal and glial regulatory programs as plausible contributors to LBP genetic susceptibility and highlight CLEC18A, QPRT, and GMPPB as higher-priority non-MHC candidates with moderate colocalization support. The results provide a spatially contextualized framework for candidate prioritization in LBP, while emphasizing the need for larger cell-type-specific eQTL resources and functional validation before therapeutic or mechanistic conclusions can be drawn.

Mendelian randomization↗
PubMed2026

A spatially resolved genomic-molecular atlas of human white-matter microstructure.

Human white matter has been linked to inherited variation, circulating molecular state and brain disease, but these layers have rarely been mapped onto the same tract anatomy. Here we measured genetic effects along 6,090 atlas-aligned fiber pathways sampled at 609,000 locations in 72,185 UK Biobank participants, and integrated proteomic and metabolomic profiles within the same anatomical frame. Genetic effects were not whole-tract properties: each locus formed a spatial footprint along fiber trajectories, ranging from single locations to broad multi-tract patterns and reflecting regional polygenicity rather than tract heritability. This map identified 258, 186 and 298 previously unreported loci for fractional anisotropy, mean diffusivity and axial diffusivity; spatial patterns replicated in adults and 157 of 315 FA loci replicated in adolescence in ABCD. Mendelian randomization linked localized genetic effects to neurodegenerative and psychiatric traits, with Alzheimer's disease showing directional effects across 12 of 17 tracts. Multi-omic analyses identified 97 proteomic and 161 metabolomic associations, with the broadest signals from lipid metabolites including linoleic acid and phosphatidylcholines. The strongest lipid-metabolite and genetic signals converged in the corpus callosum, placing inherited variation, disease risk and systemic lipid metabolism on the same localized tract segments.

Journal Article↗
PubMed1996

GenomeInspector: basic software tools for analysis of spatial correlations between genomic structures within megabase sequences.

The speed of acquisition of genomic sequence data exceeds the evaluation of function of the sequences by a vast margin. Most software available for the prediction of individual features does not assess the correlation of different motifs (level 1 methods). Here, we present a second-level software package called GenomeInspector (GI) for further analysis of results obtained with level 1 methods. Our approach does not require any a priori knowledge about motif organization and was designed as a modular package with a graphical user interface. Three examples for GI application are presented.

Genome↗
PubMed2001

Spatial variability of genomic aberrations in a large glioblastoma resection specimen.

In the present study, the distribution of genetic aberrations in a glioblastoma resection specimen of unusually large size (9x8x2 cm) was investigated using comparative genomic hybridization (CGH). CGH was performed on 20 samples taken from the specimen, and the genetic aberrations found were compared with the regional histology. The samples were histopathologically graded according to WHO criteria, and a division in high- and low-grade areas and infiltration rims was made. In high-grade areas, low-grade areas as well as infiltration rims, gains on 10p11.2-pter (14/20), 11q12-q22 (6/20) and losses on 4q13-qter (9/20), 10q22-qter (8/20), 11p14-pter (5/20), 13q12-qter (7/20) were revealed. Gains on 1q21-32 (2/4) and losses on 7p21-pter (3/4) were exclusively found in the high-grade areas. In the low-grade tumor samples and in the infiltration rim, gains on 16p11.2-pter (6/16), 17p11.2-pter (6/16), 17q11.2-qter (5/16), 20q11.2-q13 (3/16) and deletions on 5q31-qter (4/16) were detected. Gains on 7q21-qter (8/11) and 8q11.2-qter (6/11), and loss of chromosome 9 (4/11) and the Y-chromosome (4/11) were found in the high-grade and low-grade samples, not in the infiltration rims. The finding of a set of identical chromosomal aberrations throughout the resection specimen, most of which have been previously reported in gliomas, confirms a mechanism of clonal tumor proliferation operative in gliomas. The previously unreported genetic alterations which were predominantly traced in the tumor rims, might reflect either selection for properties related to infiltrating behavior, or genomic instability of subclones. The findings illustrate the importance of searching for high-grade genetic aberrations in low-grade tumor samples taken from cases in which sampling error is suspected.

Brain Neoplasms↗
PubMed1987

Spatial separation of parental genomes in hybrids of somatic plant cells.

Chromosome spatial arrangements on metaphase plates of intergeneric intertribal cell hybrids of Nicotiana chinensis and Atropa belladonna as well as interspecific somatic hybrid plants of Nicotiana plumbaginifolia and Nicotiana sylvestris were analyzed. In the metaphases of the first divisions of protoplast fusion products, chromosomes of the two parents were spatially separated (segmented metaphase). In long-term cultured somatic hybrids, the topology of genome separation pattern in both callus cells and plants showed changes in form from "segmental" to "radial." Growing the hybrid cells in the presence of colchicine resulted in random chromosome arrangement both in cells directly exposed to different colchicine concentrations and in colchicine-treated cells grown in colchicine-free media. The degree of genome separation calculated for different cell clones remained constant during in vitro propagation of cells but was significantly lower for subclones derived from colchicine-treated cells. Therefore, it is concluded that spatial chromosome arrangement in metaphase is epigenetically controlled.

Journal Article↗
PubMed1991

The male-derived genome after sperm-egg fusion: spatial distribution of chromosomal DNA and paternal-maternal genomic association.

After fusion with an egg, the haploid genome of a mammalian sperm expands from a volume of a few cubic microns to a volume of several thousand cubic microns in a fully developed zygote pronucleus. Using fluorescent in situ hybridization we studied two aspects of the chromatin organization of the sperm-derived genome during this process in a model system involving fusion of human sperm with hamster eggs. We found that (a) from the beginning of sperm head decondensation to early pronuclear stages, the hybridization signal of a probe targeted to the satellite III heterochromatin of chromosome 1 appeared as an irregularly shaped domain. In fully developed pronuclei, the signal became a fiber as much as 20-fold more extended compared with interphase somatic nuclei. The signal appeared as a string of non-uniformly distributed "beads" with interspersed gaps. A similar spatial distribution and appearance recurred after the first cleavage division. (b) Male- and female-derived genomes assembled non-randomly on the first mitotic spindle, and continued to be sequestered from each other in the nuclei of two-cell stages.

Animals↗
PubMed2026

Integrative transcriptomic, spatial and functional-genomic analysis identifies a UFMylation-related vascular-stromal program and prioritizes WWTR1 in glioblastoma.

Glioblastoma (GBM) contains spatially organized stress-adaptive and vascular niches. Because transcript abundance does not measure UFM1 conjugation, we asked whether a UFMylation-related transcriptional axis identifies a reproducible tissue program and alters candidate prioritization. In 518 unique primary TCGA-GBM tumors profiled on the Affymetrix HT Human Genome U133A array, weighted gene co-expression network analysis of 8,000 variable genes yielded 12 modules. The 278-gene green module ranked first across nine prespecified traits (mean |r|=0.637). Direct overlap comprised 1/3 measurable UFMylation-core, 5/19 ER-stress/UPR, and 2/15 proteostasis genes; after excluding overlapping genes, correlations with the green eigengene remained significant (r = 0.373, 0.831, 0.639, and 0.699 for UFMylation-core, ER-stress/UPR, proteostasis, and composite scores, respectively). The green score was associated with overall survival per standard-deviation increase (HR 1.17, 95% CI 1.07-1.28), although clinical adjustment attenuated the estimate. In a 10-sample single-cell dataset, sample-level scores were higher in pericytes and endothelial cells than in malignant cells. Donor-aware IvyGAP analysis supported regional organization, whereas one Visium section showed stronger concordance with ER-stress/UPR and mesenchymal scores than with the UFMylation-core score. CellChat indicated pathway-selective rather than global remodeling of inferred vascular communication. Layer ablation moved WWTR1 from rank 48 using WGCNA alone to rank 4 overall and rank 1 among non-common-essential genes after cross-platform integration. These findings define an ER-stress/mesenchymal-weighted, UFMylation-related vascular-stromal transcriptional association and nominate WWTR1 for experimental testing.

Humans↗
PubMed2002

Representation and processing of complex DNA spatial architecture and its annotated genomic content.

This paper presents a new general approach for the spatial representation and visualization of DNA molecule and its annotated information. This approach is based on a biological 3D model that predicts the complex spatial trajectory of huge naked DNA. With such modeling, a global vision of the sequence is possible, which is different and complementary to other representations as textual, linguistics or syntactic ones. The DNA is well known as a three-dimensional structure. Whereas, the spatial information plays a great part during its evolution and its interaction with the other biological elements This work will motivate investigations in order to launch new bioinformatics studies for the analysis of the spatial architecture of the genome. Besides, in order to obtain a friendly interactive visualization, a powerful graphic modeling is proposed including DNA complex trajectory management and its annotated-based content structuring. The paper describes spatial architecture modeling, with consideration of both biological and computational constraints. This work is implemented through a powerful graphic software tool, named ADN-Viewer. Several examples of visualization are shown for various organisms and biological elements.

DNA↗
PubMed2004

Genome-wide analysis of spatial gene expression in Arabidopsis flowers.

We have compared the gene expression profiles of inflorescences of the floral homeotic mutants apetala1, apetala2, apetala3, pistillata, and agamous with that of wild-type plants using a flower-specific cDNA microarray and a whole genome oligonucleotide array. By combining the data sets from the individual mutant/wild type comparisons, we were able to identify a large number of genes that are, within flowers, predicted to be specifically or at least predominantly expressed in one type of floral organ. We have analyzed the expression patterns of several of these genes by in situ hybridization and found that they match the predictions that were made based on the microarray experiments. Moreover, genes with known floral organ-specific expression patterns were correctly assigned by our analysis. The vast majority of the identified transcripts are found in stamens or carpels, whereas few genes are predicted to be expressed specifically or predominantly in sepals or petals. These findings indicate that spatially limited expression of a large number of genes is part of flower development and that its extent differs significantly between the reproductive organs and the organs of the perianth.

Arabidopsis↗
PubMed2006

Genome-wide analysis of spatial and temporal gene expression in rice panicle development.

The basic structure of a rice inflorescence (the panicle) is determined by the pattern of branch formation, which is established at the early stages of panicle development. In this study we conducted global transcriptome profiling of the early stages of rice panicle development from phase transition to floral organ differentiation. To generate a meristem-specific gene-expression profile, shoot apical meristems (SAMs) and subsequently formed, very young panicles were collected manually and used for cDNA microarray analysis. We identified 357 out of 22,000 genes that are expressed differentially in the early stages of panicle development, and the 357 genes were classified into seven groups based on their temporal expression patterns. The most noticeable feature is that a fairly small number of genes, which are extensively enriched in transcription factors, are upregulated in the SAM immediately after phase transition. In situ hybridization analysis showed that each gene analysed exhibits a unique and interesting localization of mRNA. Remarkably, one of the transcription factors was proven to be a close downstream component of the pathway in which LAX, a major regulator of panicle branching, acts. These results suggest that our strategy--careful collection of meristems, global transcriptome analysis and subsequent in situ hybridization analysis--is useful not only to obtain a genome-wide view of gene expression, but also to reveal genetic networks controlling rice panicle development.

Gene Expression Profiling↗
PubMed2004

The spatial organization of the genome in mammalian cells.

A number of recent studies have indicated that the location of a given mammalian chromosome within the interphase nucleus is related to its size, whereas other work has implicated a chromosome's gene density as a factor. Recent investigations of the degree to which an ordered arrangement of mitotic chromosomes on the metaphase plate is inherited and perpetuated during successive cell cycles have also yielded somewhat controversial results. The arrangement of chromosomes in the nucleus also has been investigated by the analysis of chromosomal translocations, with some surprising recent findings.

Animals↗