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PubMed2026

Multiomics approaches to cardiovascular disease: technological innovations and clinical translation.

Cardiovascular diseases (CVDs) remain the leading cause of global morbidity and mortality, reflecting a persistent gap between clinical phenotyping and the molecular mechanisms that govern disease initiation, progression, and interindividual variability. Recent advances in emerging technologies have fundamentally reshaped cardiovascular physiology by enabling high-resolution, cross-layer profiling of the heart and vasculature across genomic, epigenomic, transcriptomic, proteomic, metabolomic, lipidomic, glycomic, and fluxomic layers, increasingly at single-cell and spatial resolution. These approaches reveal CVD as a coordinated, multilayered process driven by dynamic interactions among cell types, regulatory programs, and metabolic states, rather than isolated gene-level defects. In this review, we synthesize how emerging multiomic, computational, and functional genomic technologies are redefining the study of cardiovascular disease across molecular, cellular, and tissue levels. We highlight recent innovations in single-cell and spatial atlases, long-read sequencing, proteomics and metabolomics, integrative data modeling, and functional omics approaches, including genome-scale perturbation screens and single-cell perturbation frameworks. These platforms enable mechanistic dissection of regulatory circuits, distinguish primary disease drivers from secondary adaptations, and directly assess therapeutic reversibility, advancing the field beyond associative biomarker discovery toward mechanism-guided target prioritization. We further discuss key methodological and translational challenges accompanying high-dimensional cardiovascular data, including preanalytical variability, control selection, temporal misalignment across molecular layers, population diversity, and reference bias. By integrating technological innovation with computational rigor and functional validation, this review frames emerging omics-enabled strategies as a unified, physiologically grounded framework for translating molecular insight into clinically meaningful cardiovascular phenotypes and advancing precision cardiovascular medicine.

Humans↗
PubMed1995

Genomic regions required for morphogenesis of the Drosophila embryonic midgut.

The Drosophila midgut is an excellent system for studying the cell migration, cell-cell communication, and morphogenetic events that occur in organ formation. Genes representative of regulatory gene families common to all animals, including homeotic, TGF beta, and Wnt genes, play roles in midgut development. To find additional regulators of midgut morphogenesis, we screened a set of genomic deficiencies for midgut phenotypes. Fifteen genomic intervals necessary for proper midgut morphogenesis were identified, three contain genes already known to act in the midgut. Three other genomic regions are required for formation of the endoderm or visceral mesoderm components of the midgut. Nine regions are required for proper formation of the midgut constrictions. The E75 ecdysone-induced gene, which encodes a nuclear receptor superfamily member, is the relevant gene in one region and is essential for proper formation of midgut constrictions. E75 acts downstream of the previously known constriction regulators or in parallel. Temporal hormonal control may therefore work in conjunction with spatial regulation by the homeotic genes in midgut development. Another genomic region is required to activate transcription of the homeotic genes Antp and Scr specifically in visceral mesoderm. The genomic regions identified by this screen provide a map to novel midgut development regulators.

Animals↗
PubMed2024

Integration of Imaging-based and Sequencing-based Spatial Omics Mapping on the Same Tissue Section via DBiTplus.

Spatially mapping the transcriptome and proteome in the same tissue section can significantly advance our understanding of heterogeneous cellular processes and connect cell type to function. Here, we present Deterministic Barcoding in Tissue sequencing plus (DBiTplus), an integrative multi-modality spatial omics approach that combines sequencing-based spatial transcriptomics and image-based spatial protein profiling on the same tissue section to enable both single-cell resolution cell typing and genome-scale interrogation of biological pathways. DBiTplus begins with in situ reverse transcription for cDNA synthesis, microfluidic delivery of DNA oligos for spatial barcoding, retrieval of barcoded cDNA using RNaseH, an enzyme that selectively degrades RNA in an RNA-DNA hybrid, preserving the intact tissue section for high-plex protein imaging with CODEX. We developed computational pipelines to register data from two distinct modalities. Performing both DBiT-seq and CODEX on the same tissue slide enables accurate cell typing in each spatial transcriptome spot and subsequently image-guided decomposition to generate single-cell resolved spatial transcriptome atlases. DBiTplus was applied to mouse embryos with limited protein markers but still demonstrated excellent integration for single-cell transcriptome decomposition, to normal human lymph nodes with high-plex protein profiling to yield a single-cell spatial transcriptome map, and to human lymphoma FFPE tissue to explore the mechanisms of lymphomagenesis and progression. DBiTplusCODEX is a unified workflow including integrative experimental procedure and computational innovation for spatially resolved single-cell atlasing and exploration of biological pathways cell-by-cell at genome-scale.

Journal Article↗
PubMed2024

Integration of Imaging-based and Sequencing-based Spatial Omics Mapping on the Same Tissue Section via DBiTplus.

Spatially mapping the transcriptome and proteome in the same tissue section can significantly advance our understanding of heterogeneous cellular processes and connect cell type to function. Here, we present Deterministic Barcoding in Tissue sequencing plus (DBiTplus), an integrative multi-modality spatial omics approach that combines sequencing-based spatial transcriptomics and image-based spatial protein profiling on the same tissue section to enable both single-cell resolution cell typing and genome-scale interrogation of biological pathways. DBiTplus begins with in situ reverse transcription for cDNA synthesis, microfluidic delivery of DNA oligos for spatial barcoding, retrieval of barcoded cDNA using RNaseH, an enzyme that selectively degrades RNA in an RNA-DNA hybrid, preserving the intact tissue section for high-plex protein imaging with CODEX. We developed computational pipelines to register data from two distinct modalities. Performing both DBiT-seq and CODEX on the same tissue slide enables accurate cell typing in each spatial transcriptome spot and subsequently image-guided decomposition to generate single-cell resolved spatial transcriptome atlases. DBiTplus was applied to mouse embryos with limited protein markers but still demonstrated excellent integration for single-cell transcriptome decomposition, to normal human lymph nodes with high-plex protein profiling to yield a single-cell spatial transcriptome map, and to human lymphoma FFPE tissue to explore the mechanisms of lymphomagenesis and progression. DBiTplusCODEX is a unified workflow including integrative experimental procedure and computational innovation for spatially resolved single-cell atlasing and exploration of biological pathways cell-by-cell at genome-scale.

Journal Article↗
PubMed2006

Studying statistical properties of regulatory DNA sequences, and their use in predicting regulatory regions in the eukaryotic genomes.

There are no well-known properties in regulatory DNA analogous to those in coding sequences; their spatial location is not regular, the consensus regulatory elements are often degenerate and there are no understandable rules governing their evolution. This makes it difficult to recognize regulatory regions within genome. We review developments in the statistical characterization of regulatory regions and methods of their recognition in eukaryotic genomes.

Computational Biology↗
PubMedDate not supplied

Influence of parental chromosomes on spatial specificity in androgenetic----parthenogenetic chimaeras in the mouse.

The presence of both parental genomes is essential for development to term in the mouse embryo probably because of germline-specific modifications of homologous chromosomes. Neither androgenetic nor parthenogenetic embryos can by themselves develop to term; any post-implantation embryos they produce have opposite phenotypes, which reflects the presence of complementary information in parental chromosomes. The development of androgenetic----parthenogenetic chimaeras is of considerable interest because in this case both parental chromosomes are available even though they are in separate cells. We demonstrate here that in post-implantation chimaeric fetuses, the expression of parental information results in spatial specificity so that parthenogenetic cells are confined to the embryo but the trophoblast consists almost entirely of androgenetic cells. The yolk sac contains both cell types. However, there is incomplete functional complementation because the chimaeras do not reach term. Although failure to reach term may occur partly because of inadequate intermingling and interactions between embryonic cells, it is more likely that further control of mouse development depends on the presence of both sets of chromosomes within the same cells.

Animals↗
PubMed2003

Nucleolar clustering of dispersed tRNA genes.

Early transfer RNA (tRNA) processing events in Saccharomyces cerevisiae are coordinated in the nucleolus, the site normally associated with ribosome biosynthesis. To test whether spatial organization of the tRNA pathway begins with nucleolar clustering of the genes, we have probed the subnuclear location of five different tRNA gene families. The results show that tRNA genes, though dispersed in the linear genome, colocalize with 5S ribosomal DNA and U14 small nucleolar RNA at the nucleolus. Nucleolar localization requires tRNA gene transcription-complex formation, because inactivation of the promoter at a single locus removes its nucleolar association. This organization of tRNA genes must profoundly affect the spatial packaging of the genome and raises the question of whether gene types might be coordinated in three dimensions to regulate transcription.

Cell Nucleolus↗
PubMed2004

Evaluation of genetic patterns in different tumor areas of intermediate-grade prostatic adenocarcinomas by high-resolution genomic array analysis.

Prostate cancer is known for its highly heterogeneous histological appearance. Data concerning the cytogenetic content of areas with different histology are sparse. We have genetically evaluated 10 prostatic adenocarcinomas with intermediate histopathological grades (Gleason score 7) that showed two distinctive growth patterns with different pathologies, that is, Gleason grades 3 and 4 (G3 and G4). The G3 and G4 tumor specimens were taken from spatially separated regions within the cancer mass. Array-based comparative genomic hybridization (aCGH) was performed to obtain genotypes from the 10 pairs of G3 and G4 cancer areas. The cancer DNAs were retrieved from formalin-fixed and paraffin-embedded tissues allowing optimal recognition and selection of target cells. A genome-wide 2,400-element BAC array that provided high-resolution detection of both deletions and amplifications was used. In the 20 G3 and G4 areas, 252 genomic aberrations (88 gains, 164 deletions) were noted, of which 86 were concurrent in G3 and G4 areas (34% overlap). Ninety-five of the 252 alterations were defined by a single BAC clone (54 gains, 41 deletions). Overlapping changes were more frequent for deletions (46%) than for gains (13%). Frequent coinciding deletions (> or = 20% of tumors) were seen on 8p (60%), 6q (30%), 1p (20%), 2q (20%), proximal 8q (20%), 10q (20%), 13q (20%), 16q (20%), and 18q (20%). A frequent overlapping gain (> or = 20% of tumors) was detected on distal 13q (20%). The patterns of imbalance could be found to coincide in the G3 and G4 areas of the majority of cancers. Array-based CGH can be used as a tool for the evaluation of genetic patterns in prostate cancer.

Adenocarcinoma↗
PubMed2026

highSpaClone enables copy number alteration inference and tumor subclone analysis for high-resolution spatial transcriptomics.

High-resolution spatially resolved transcriptomics (SRT) offers unprecedented opportunities to investigate tumor heterogeneity but poses substantial computational and analytical challenges. Here, we present highSpaClone, a computational framework for copy number alteration (CNA) inference and tumor subclone identification from high-resolution SRT data across multiple spatial scales. By integrating spatial constraints into CNA estimation and clonal clustering, highSpaClone enables neighboring spatial locations to share information, thereby improving the robustness of genomic signals and the accuracy of subclone delineation. Across multiple Xenium and Visium HD datasets, highSpaClone revealed unique transcriptional programs, clonal evolutionary trajectories, and distinct tumor-microenvironment interactions. Furthermore, in human colorectal cancer samples, highSpaClone detected CNA events in histologically normal epithelial regions, highlighting early genomic alterations associated with field cancerization. These findings establish highSpaClone as a scalable framework for studying clonal architecture and tumor evolution.

CP: cancer biology↗
PubMed2005

Decoding cis-regulatory systems in ascidians.

Ascidians, or sea squirts, are lower chordates, and share basic gene repertoires and many characteristics, both developmental and physiological, with vertebrates. Therefore, decoding cis-regulatory systems in ascidians will contribute toward elucidating the genetic regulatory systems underlying the developmental and physiological processes of vertebrates. cis-Regulatory DNAs can also be used for tissue-specific genetic manipulation, a powerful tool for studying ascidian development and physiology. Because the ascidian genome is compact compared with vertebrate genomes, both intergenic regions and introns are relatively small in ascidians. Short upstream intergenic regions contain a complete set of cis-regulatory elements for spatially regulated expression of a majority of ascidian genes. These features of the ascidian genome are a great advantage in identifying cis-regulatory sequences and in analyzing their functions. Function of cis-regulatory DNAs has been analyzed for a number of tissue-specific and developmentally regulated genes of ascidians by introducing promoter-reporter fusion constructs into ascidian embryos. The availability of the whole genome sequences of the two Ciona species, Ciona intestinalis and Ciona savignyi, facilitates comparative genomics approaches to identify cis-regulatory DNAs. Recent studies demonstrate that computational methods can help identify cis-regulatory elements in the ascidian genome. This review presents a comprehensive list of ascidian genes whose cis-regulatory regions have been subjected to functional analysis, and highlights the recent advances in bioinformatics and comparative genomics approaches to cis-regulatory systems in ascidians.

Animals↗
PubMed1996

The nucleotype, the natural karyotype and the ancestral genome.

New knowledge of synteny and collinearity promises to unify genetics and to affect our perception of higher order genome structure. This exciting new synthetic approach emphasizes genomic similarities rather than diversity. Two other aspects of genomic form and organisation, offering potentially unifying concepts in genome studies are: the nucleotype, and the natural karyotype. Genome size varies greatly between eukaryotes, and shows many strikingly precise correlations with phenotypic characters, independent of information encoded in DNA. Such nucleotypic correlations, based on biophysical absolutes, apply to all species, irrespective of genome size or chromosome number, and set limits on the range of phenotypes which can be expressed by genic control. Thus, knowledge of nucleotypic effects has considerable predictive value which can help to unify our understanding of genomes. Other studies of reconstructed nuclei have shown that: (1) the basic haploid genome exists as a real structural unit in nuclear architecture; while (2) the mean spatial arrangement of its heterologues also exists as a natural karyotype which is predictable using a simple model. Recently reported conceptual alignments of the maize genomes, which reflect the circularized ancestral grass genome, show interesting similarities with the orders of centromeres in their natural karyotypes predicted by the Bennett model. The basis of this phenomenon (if repeated in other species), and of selection which retains the ancestral genome form despite changes in basic chromosome number, may need to be explained. Perhaps the overall 3-D structure of the genome has some critical functional significance, essential for development. If so, a knowledge of this common structure would further unify our understanding of genomes and their evolution.

Biological Evolution↗
PubMed1998

Large-scale screening for developmental genes in embryonic stem cells and embryoid bodies using retroviral entrapment vectors.

Mammalian development is orchestrated by a variety of cellular proteins with expression that is regulated precisely. Although some of the genes encoding these factors have been identified, largely by homology to those of simpler organisms, the majority of them presumably remain unknown. We report here on the results of a large-scale genetic screen that can potentially lead to the identification of many of these unidentified genes in mice. The method we developed takes advantage of the fact that many of the factors that regulate early development are expressed at highly specific stages of early embryogenesis. We therefore established a method for tagging candidate developmental genes by virtue of their expression in a stage-specific manner during formation of embryoid bodies without a bias for their expression in undifferentiated embryonic stem (ES) cells. Of 2,400 ES cell clones with random insertions of retroviral vectors carrying a human placental alkaline phosphatase reporter gene (AP), 41 clones exhibited stage-specific reporter gene expression during embryoid body formation. The majority of these insertions were in genes that are not expressed in undifferentiated ES cells. Eleven ES cell clones with characteristic patterns of AP reporter gene expression in vitro were chosen for further examination in vivo for AP expression in developing embryos. Ten ES cell clones exhibited AP expression between day 7.5 and day 10.5 of development. Clones that showed restricted reporter gene expression in vitro also exhibited similar temporally and spatially restricted AP expression in vivo. Sequence analysis of genomic DNA flanking several vector insertions and corresponding cDNAs suggested that several of the insertions identified a previously unidentified gene. Thus, screening for reporter gene expression during embryoid body formation provides an efficient means of enriching clones that contain vector insertions into potentially novel genes that are important for regulating different stages of early postimplantation development.

Alkaline Phosphatase↗
PubMed2000

Pre-pleistocene refugia and differentiation between populations of the caucasian salamander (Mertensiella caucasica).

A 350-bp fragment of the mitochondrial cytochrome-b gene was sequenced in the Caucasian salamander, Mertensiella caucasica, representing 10 populations from across its range along the Black Sea coast. Five haplotypes were discovered among 65 fragments analyzed, differing at 2-50 positions. The highest differentiation between haplotypes was observed in animals from the eastern part of the species' range (Borjomi) compared to those from the remainder of the species' range. Randomly amplified nuclear DNA revealed a pattern of spatial genetic variation similar to that of the mitochondrial genome. M. caucasica, as currently known, represents two evolutionary lineages that evolved independently, perhaps since the lower Pliocene. These lineages represent taxa, possibly to be described as species, distributed in the Borjomi area in central Georgia and in southwestern Georgia and northeastern Turkey. The multivariate analysis of morphological data did not reveal significant differences between the taxa. However, substantial morphological differentiation was observed within both lineages, showing parallel patterns in body proportions and coloration patterns. This variation is possibly associated with extant ecological conditions. Salamanders with reduced pigmentation from southwestern Georgia were not genetically distinguishable from neighboring populations.

Animals↗
PubMed2026

Omics in optic neuropathies: From molecular landscapes to personalized therapeutics.

Optic neuropathies comprise a heterogeneous group of disorders involving transient or permanent injury to retinal ganglion cells (RGCs) and their axons. Clinically, these neurodegenerative conditions manifest as dyschromatopsia, decreased visual acuity, and visual field defects, and in severe cases may ultimately lead to blindness and disability. The marked heterogeneity across disease subtypes, incompletely understood etiologies, and complex pathogenic mechanisms pose substantial challenges to precise diagnosis and effective treatment. Recent advances in omics technologies - including genomics, transcriptomics, proteomics, metabolomics, lipidomics, single-cell and spatial sequencing, and integrative multi-omics approaches - have ushered optic nerve degenerative disease research into an era of high-resolution comprehensive investigation. In this review, we summarize representative applications of omics approaches to elucidate genetic alterations, signaling dysregulation, metabolic reprogramming, and immune responses in optic neuropathies. We further discuss the emerging potential of multi-omics in identifying early diagnostic biomarkers and informing individualized therapeutic strategies. Finally, we provide a forward-looking perspective on the future trajectory of omics technologies and their prospects in both fundamental research and clinical translation, with the overarching aim of accelerating the bench-to-bedside transition in this critical eye disease field.

biomarkers↗
PubMed2004

The MTG proteins: chromatin repression players with a passion for networking.

The human myeloid translocation genes (MTGs) encode a family of proteins with a modular structure that can be traced to the Drosophila protein nervy. The nuclear MTGs can mediate the formation of complex protein networks among nuclear corepressors (Sin3a, N-CoR, SMRT), chromatin-modifying enzymes (histone deacetylases), and DNA-binding transcription factors. Hierarchical modulation of repression at target genes by MTG protein complexes is likely required for fine spatial and temporal gene regulation during development and differentiation. Genomic changes can disrupt these sophisticated protein networks and underlie novel pathogenic causes of cancer and neurodegeneration.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Small animal PET.

Positron emission tomography (PET) has well-established strengths which are commonly exploited in human clinical research. Not least of these are its dynamic and quantitative capabilities. The recent growth in small animal PET, spurred on by technological developments and an interest in the application of imaging to the field of genomics in mice, has seen impressive improvements in image spatial resolution. The availability of commercial small animal PET scanners has meant a broadening of the user base away from PET development environments and into experimental laboratories. This paper will review these developments and assess the impact on overall data quality.

Animals↗
PubMed2005

Detailed analysis of the genetic evolution of influenza virus during the course of an epidemic.

The genetic variability of influenza virus is usually studied with sequences selected over numerous years and countries, and rarely within a single season. Here we examined the viral evolution and the correlation between genetic and clinical features during an epidemic. From a French prospective household-based study in 1999-2000, 99 infected patients were randomly selected. The HA1 genomic domain was sequenced. Phylogenetic analysis showed the existence of two groups of A/H3N2 viruses. We found no distinct pattern of genomic evolution within either group according to time. A spatial correlation with the nucleotide distances was shown. The average nucleotide diversity was 3.4x10-3 nucleotides per site, and did not differ between the groups. A lower number of segregating sites was observed in patients who experienced influenza-like symptoms during the previous epidemic. These results suggest that the influenza virus undergoes regular HA1 nucleotide changes, but without clonal expansion of mutant strains within a single epidemic.

Adult↗
PubMed2000

Signal transduction in mammary tumorigenesis: a transgenic perspective.

A number of genes have been implicated in breast cancer development, yet few have been demonstrated to play causative roles in mammary tumor formation. The advent of transgenic mouse and embryonic stem cell technologies now permits manipulation of the mouse genome in such a way as to temporally and spatially control a gene product's expression. Thus, the basic researcher now can directly assess the involvement of particular genes in tumorigenesis and disease progression and, in the process, to develop mouse models of human genetic disease. The utility of such technologies is emphasized in transgenic mice expressing genes thought to play important roles in the initiation and progression of mammary carcinomas. As these transgenic strains have been the subject of several reviews, here we focus on two mouse mammary tumor models, Polyomavirus middle T antigen and the Neu/ErbB-2 receptor tyrosine kinase, which are most amenable to study specific signaling pathways in process of mammary tumorigenesis.

Animals↗