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PubMed2026

High-Content CRISPR Screening: Methods and Applications.

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening has become a central technology in functional genomics, enabling genome-scale interrogation via pooled perturbations. Early CRISPR screens employed survival or simple phenotypic readouts to identify essential genes and drug resistance mechanisms. However, as biological questions have shifted toward understanding regulatory networks, cellular heterogeneity, and context-dependent gene functions, there has been increasing demand for screening strategies capable of capturing complex cellular phenotypes beyond cell fitness. Recent advances in single-cell sequencing, high-content imaging, and spatial transcriptomics have expanded the resolution of CRISPR screening by enabling multidimensional phenotypic characterization following genetic perturbation. By integrating pooled perturbations with diverse readouts, these approaches systematically map targeted gene edits to transcriptional states, cellular phenotypes, and microenvironmental contexts. Meanwhile, innovations in library design, delivery, and computational pipelines have further improved the robustness and interpretability of high-content screening platforms. This review synthesizes the methodological evolution of CRISPR screening, emphasizing advances in perturbation strategies, delivery systems, and multimodal readouts. Representative applications spanning oncology, immunotherapy, developmental biology, neurobiology, and infectious diseases are delineated to demonstrate refined gene network annotations. Additionally, existing technical bottlenecks, such as scalability, cost constraints, and in vivo limitations, are critically assessed. Finally, future directions are proposed to facilitate the development of precise medicine.

CRISPR screening↗
PubMed2026

Unraveling the epidemiological and dispersal dynamics of the 2024-2025 chikungunya virus epidemic on Réunion Island.

Réunion Island experienced a massive chikungunya virus epidemic in 2024-2025, with >54,000 confirmed cases. This is the second major chikungunya epidemic on the island, following the first one that peaked 20 years ago. It has been asserted that this new outbreak finds its origin in a single introduction event into the island, offering an opportunity to exploit viral genomic data to understand the epidemiological and dispersal dynamics of the introduced transmission chain. We sequenced >3,000 viral genomes collected during the epidemic. Harnessing this genomic dataset, we used several phylogeographic and phylodynamic approaches to unravel the paths taken by the transmission chain and the external factors that might have impacted its dispersal and epidemiological dynamics on the island. Our analyses highlight a dispersal pattern in line with a gravity-model dynamic with viral transition events being more frequent from and toward more populated areas. Our analyses reveal that the transmission chain was overall spatially intermixed, with frequent exchanges among residential areas. In addition, we show that the temporal dynamic and intensity of the epidemic were associated with climatic variables, namely temperature and precipitation. Our results also show that in theory, the population immunity-resulting from this epidemic and the previous one (2005-2006)-could be sufficient to explain on its own the decrease in the transmission rate that led to the end of the epidemic. While a short-term resurgence cannot be excluded, the risk of a large-scale circulation of the virus in the human population appears therefore relatively limited in the upcoming seasons.

Reunion↗
PubMed1998

Genomic structure and expression sites of three gonadotropin-releasing hormone genes in one species.

In the teleost fish, Haplochromis burtoni, gonadotropin-releasing hormone (GnRH) peptide has been localized to three distinct regions in the brain. Each GnRH population is associated with expression of a distinct cDNA as previously described. Here we report the complete genomic sequences encoding these three forms and compare their structural organization, putative regulatory elements, and expression patterns in the body. All three genes share a common structure of four exons: the first exon encodes the 5' untranslated region; the second exon encodes the signal sequence, GnRH decapeptide, and the 5' end of the GnRH-associated peptide (GAP); the third exon consists entirely of GAP coding sequence; and the fourth exon encodes the 3' end of GAP and the 3' untranslated region. Each of the three GnRH genes has been shown previously to have a distinct spatial expression pattern in the brain, and here we use reverse transcription and cDNA amplification to demonstrate that each gene is expressed in the body. The gene encoding the releasing form, ¿Ser8¿GnRH, is expressed in the heart, liver, spleen, kidney, and testis, as well as in the preoptic area. The ¿His5Trp7Tyr8¿GnRH gene is expressed in the testis as well as in the midbrain. The ¿Trp7Leu8¿GnRH gene is expressed in the testis and the terminal nerve area. We examined the 500 bp upstream of exon 1 in all three H. burtoni genes and identified putative binding sites for glucocorticoid receptor, androgen receptor, and progesterone receptor, as well as the transcription factors Ap-1 and Sp-1. The genomic sequence encoding the terminal nerve form of GnRH (i.e., ¿Trp7Leu8¿GnRH) in H. burtoni is remarkably similar to that encoding the presumed releasing form of GnRH in salmonids, especially in the 3' intergenic region. Taken together with phylogenetic and mRNA localization data in salmonids, these data suggest that the gene encoding the releasing form of GnRH in salmonids may not yet be described.

Animals↗
PubMed2001

A family of proteins related to Spätzle, the toll receptor ligand, are encoded in the Drosophila genome.

The Drosophila gene Spätzle encodes the activating ligand for the Toll receptor. This signaling pathway is required for dorso-ventral patterning in the early embryo and an antifungal immune response in larvae and adults. The genome sequence of Drosophila shows that there are a total of eight Toll-like receptors and these may function in other aspects of embryonic development and innate immunity. Here we describe five Drosophila homologues of Spätzle (Spz2-6) found using an iterative searching method. All five appear to encode proteins containing neurotrophin-like cystine-knot domains. In addition, most retain a characteristic intron-exon structure shared with the prototype Spätzle gene. This provides evidence that the family arose by ancient gene duplication events and indicates that the gene products may represent activating ligands for corresponding Toll receptors. Expression studies show that only Spz4 is expressed strongly in larvae and adults and thus may be involved in an ancillary antifungal response mediated by Toll-5. By contrast, Spz6 shows a complex spatial and temporally regulated expression pattern in the late embryo. Thus the new Toll/Spätzle families of signaling molecules may have important roles in other aspects of development and immunity.

Amino Acid Sequence↗
PubMed2006

High rate of chimeric gene origination by retroposition in plant genomes.

Retroposition is widely found to play essential roles in origination of new mammalian and other animal genes. However, the scarcity of retrogenes in plants has led to the assumption that plant genomes rarely evolve new gene duplicates by retroposition, despite abundant retrotransposons in plants and a reported long terminal repeat (LTR) retrotransposon-mediated mechanism of retroposing cellular genes in maize (Zea mays). We show extensive retropositions in the rice (Oryza sativa) genome, with 1235 identified primary retrogenes. We identified 27 of these primary retrogenes within LTR retrotransposons, confirming a previously observed role of retroelements in generating plant retrogenes. Substitution analyses revealed that the vast majority are subject to negative selection, suggesting, along with expression data and evidence of age, that they are likely functional retrogenes. In addition, 42% of these retrosequences have recruited new exons from flanking regions, generating a large number of chimerical genes. We also identified young chimerical genes, suggesting that gene origination through retroposition is ongoing, with a rate an order of magnitude higher than the rate in primates. Finally, we observed that retropositions have followed an unexpected spatial pattern in which functional retrogenes avoid centromeric regions, while retropseudogenes are randomly distributed. These observations suggest that retroposition is an important mechanism that governs gene evolution in rice and other grass species.

Evolution, Molecular↗
PubMed1992

Spatial and temporal expression of the I factor during oogenesis in Drosophila melanogaster.

The I factor is a functional non-viral retrotransposon, or LINE, from Drosophila melanogaster. Its mobility is associated with the I-R hybrid dysgenesis. In order to study the expression pattern of this LINE in vivo, a translational fusion between the first ORF of the I factor and the lacZ gene of Escherichia coli has been carried out and introduced in the genome of reactive (R) flies. Homozygous transgenic Drosophila lines have been established and analysed. ORF1 expression is limited to germ-line cells (nurse cells and oocyte) between stage 2 and 10 of oogenesis. No somatic expression is found. Position effects may limit the level of expression of a given transgene but do not modify its basic pattern of expression during the development of the fly. This reproducible control demonstrates both that I factor is driven by its own promoter, probably the internal one suggested by Mizrokhi et al. (Mizrokhi, L.J., Georgevia, S.G. and Ilying, Y.V. (1988). Cell 54, 685-691), and that tissue-specific regulatory sequences are present in the 5' untranslated part of the I factor. The nuclear localization of the fusion protein reveals the presence of nuclear localization signals (NLS) in the ORF1-encoded protein correlating with the possible structural and/or regulatory role of this protein. This expression is restricted to dysgenic and reactive females, and is similar in the two conditions. All the results obtained in this work suggest that I factor transposition occurs as a meiotic event, between stage 2 and 10 of the oogenesis and is regulated at the transcriptional level. It also appears that our transgene is an efficient marker to follow I factor expression.

Animals↗
PubMed1995

Two forms of Xenopus nuclear factor 7 have overlapping spatial but different temporal patterns of expression during development.

Xenopus nuclear factor 7 (xnf7) is a maternal gene product that functions in the determination of the dorsal-ventral body axis. We have cloned two xnf7 cDNAs, xnf7-O and xnf7-B, that have a different temporal pattern of expression. The cDNAs differ by 39 amino acid residues scattered throughout the molecule. Most of the changes were conservative in nature. Using gene specific probes we found that xnf7-O transcripts were abundant in oocytes and decreased until the neurula stage, after which they increased in abundance. Xnf7-B transcripts were in low abundance in oocytes and were expressed at high levels at the neurula stage and in adult brain. Both xnf7-O and xnf7-B transcripts at the neurula stage were localized in the dorsal region of the embryo, including the neural folds and somites. Xnf7 was not expressed in ventralized embryos that lacked dorsal structures, thereby substantiating its dorsal localization in the embryo. The promoter region of the xnf7-O gene does not possess a TATA box but does contain E2F, USF, Sp1-like and AP1 binding sites within the first 421 bp from the transcription initiation site. A 62 bp fragment of the xnf7-O promoter containing the Sp1-like and E2F sites can direct proper spatial expression of a transgene in embryos.

Animals↗
PubMed2026

Predictive biomarkers in cancer immunotherapy for genitourinary malignancies.

Immunotherapy has transformed the management of genitourinary cancers, offering durable responses in selected patient groups. However, the clinical benefit of immune checkpoint inhibitors varies significantly across renal cell carcinoma, urothelial carcinoma, and prostate cancer, underscoring the need for reliable predictive biomarkers. This review summarizes current knowledge on established and emerging biomarkers, including PD L1 expression, tumor mutational burden, molecular subtypes, genomic alterations, tumor microenvironment characteristics, circulating biomarkers, microbiome influences, and multi omic integrative approaches. We discuss their potential clinical relevance, limitations, and applicability across different tumor types. Future directions emphasize the development of composite biomarkers, standardization of testing platforms, real time monitoring strategies, and the integration of advanced technologies such as artificial intelligence and spatial profiling. Understanding and validating these biomarkers will be essential for optimizing personalized immunotherapy in genitourinary cancers.

Circulating tumor DNA↗
PubMed2026

FAP+ pericyte-like cells promote monocyte differentiation into tumor-associated macrophages in glioblastoma.

Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by profound immunosuppression that facilitates tumor progression and promotes therapeutic resistance. Fibroblast activation protein (FAP), a recognized theranostic target in multiple cancers, is upregulated in GBM and predominantly expressed by pericyte-like stromal cells. Here we identify a role for FAP⁺ pericyte-like cells in shaping the GBM immune microenvironment through monocyte recruitment and differentiation. Analysis of The Cancer Genome Atlas (TCGA) datasets, supported by reverse-transcription quantitative PCR and immunohistochemistry, revealed that elevated FAP expression-serving as a proxy for the abundance of FAP⁺ pericyte-like cells-is associated with an immune-enriched tumor microenvironment characterized by higher macrophage abundance and elevated expression of M2 polarization markers. Spatial analyses, including immunofluorescence and spatial transcriptomics, demonstrated that immunosuppressive macrophages preferentially localize in proximity to FAP⁺ pericytes. Single-cell RNA sequencing identified these FAP⁺ cells as a distinct perivascular stromal subset with a unique expression pattern of extracellular matrix components and cytokines, including CCL2 and CSF1, with corresponding receptors expressed on myeloid cells. Functional assays using patient-derived FAP⁺ pericyte-like cells confirmed their ability to attract monocytes via soluble mediators and to promote their differentiation and polarization into tumor-associated macrophages with immunoregulatory features, partly mediated by the CSF1-CSF1R axis. Orthotopic co-implantation experiments in mice further supported their capacity to enhance myeloid infiltration in vivo. Consistent with these biological effects, a transcriptional signature characteristic of FAP⁺ pericytes correlated with worse overall survival in patients with GBM. Together, these findings position FAP⁺ pericyte-like cells as modulators of the GBM immune landscape, fostering a tumor-permissive niche by promoting the differentiation of circulating monocytes into immunoregulatory macrophages. Targeting this stromal population may offer new therapeutic avenues to reprogram tumor-associated immune responses in GBM.

Journal Article↗
PubMed2004

The phylogeography of human viruses.

Viruses, especially those with RNA genomes, represent ideal organisms to study the dynamics of microevolutionary change. In particular, their rapid rate of nucleotide substitution means that the epidemiological processes that shape their diversity act on the same time-scale as mutations are fixed in viral populations. Consequently, the branching structure of virus phylogenies provides a unique insight into spatial and temporal dynamics. Herein, I describe the key processes in virus phylogeography. These are generally associated with the relative rates of dispersal among populations and virus-host codivergence (vicariance), and the division between acute (short-term) and persistent (long-term) infections. These processes will be illustrated by important human viruses - HIV, dengue, rabies, polyomavirus JC and human papillomavirus - which display varying spatial and temporal structures and virus-host relationships. Key research questions for the future will also be established.

Dengue Virus↗
PubMed2026

SIVA: diagonal integration of spatial multi-omics data via spatially informed variational autoencoders and anchor guidance.

MOTIVATION: Understanding cellular states and regulatory programs requires integrative analysis of multiple omics layers. Although recent spatial sequencing technologies allow molecular profiling of cells within their tissue context, paired spatial multi-omics assays are still limited by technical complexity and cost. This creates a pressing need for diagonal integration methods that enable joint analysis of unpaired spatial omics datasets. RESULTS: We propose SIVA, a deep generative framework based on Spatially-Informed Variational Autoencoders with Anchor Guidance, for diagonal integration of spatial multi-modal data. SIVA employs modality-specific variational autoencoders (VAEs) with a hybrid latent embedding that integrates Gaussian process and standard Gaussian priors, enabling joint modeling of spatially structured variation and dominant underlying data distributions across modalities. To facilitate cross-modal alignment in the absence of one-to-one cell correspondence, SIVA adopts a dual integration strategy combining global distribution alignment via Maximum Mean Discrepancy and local correspondence guidance using mutual nearest neighbor anchors. Extensive experiments across multiple cross-slice integration scenarios demonstrate that SIVA achieves robust and accurate integration of unpaired spatial omics datasets, consistently outperforming existing methods. AVAILABILITY AND IMPLEMENTATION: The source codes are available at https://github.com/PelenJiang/SIVA.

Autoencoder↗
PubMed2006

jPREdictor: a versatile tool for the prediction of cis-regulatory elements.

Gene regulation is the process through which an organism effects spatial and temporal differences in gene expression levels. Knowledge of cis-regulatory elements as key players in gene regulation is indispensable for the understanding of the latter and of the development of organisms. Here we present the tool jPREdictor for the fast and versatile prediction of cis-regulatory elements on a genome-wide scale. The prediction is based on clusters of individual motifs and any combination of these into multi-motifs with selectable minimal and maximal distances. Individual motifs can be of heterogenous classes, such as simple sequence motifs or position-specific scoring matrices. Cluster scores are weighted occurrences of multi-motifs, where the weights are derived from positive and negative training sets. We illustrate the flexibility of the jPREdictor with a new predic-tion of Polycomb/Trithorax Response Elements in Drosophila melanogaster. jPREdictor is available as a graphical user interface for online use and for download at http://bibiserv.techfak.uni-bielefeld.de/jpredictor.

Animals↗
PubMed1993

An upstream region of the rat spermatogenesis-specific heat-shock-like Hst70 gene confers testis-specific expression in transgenic mice.

In order to study the temporal and spatial regulation of a rat testis-specific heat-shock-like hst70 gene, an 0.8-kb fragment of its upstream DNA was fused to the lacZ gene and microinjected into one-cell murine embryos. Independent tgHST1 and tgHST2 transgenic mice strains were established, containing about 5-7 and 40-60 transgene copies/haploid genome, respectively. Enzyme assays in various tissues showed that transgene-encoded beta-galactosidase accumulates exclusively in testes of transgenic animals and cannot be detected until 16-17 days after birth. In-situ assays revealed that the enzyme accumulates mainly in pachytene primary spermatocytes. Our data complement previous studies on the endogenous rat hst70 and suggest that its 0.8-kb upstream region contains sufficient information to function as an active spermatogenesis-specific promoter.

Animals↗
PubMed1998

Genomic cis-regulatory logic: experimental and computational analysis of a sea urchin gene.

The genomic regulatory network that controls gene expression ultimately determines form and function in each species. The operational nature of the regulatory programming specified in cis-regulatory DNA sequence was determined from a detailed functional analysis of a sea urchin control element that directs the expression of a gene in the endoderm during development. Spatial expression and repression, and the changing rate of transcription of this gene, are mediated by a complex and extended cis-regulatory system. The system may be typical of developmental cis-regulatory apparatus. All of its activities are integrated in the proximal element, which contains seven target sites for DNA binding proteins. A quantitative computational model of this regulatory element was constructed that explicitly reveals the logical interrelations hard-wired into the DNA.

Animals↗
PubMed1989

Platelet-derived growth factor-inducible gene JE is a member of a family of small inducible genes related to platelet factor 4.

The platelet-derived growth factor-inducible gene JE was found to encode a 148-residue basic (pI = 10.4) secretory protein which shows striking similarity to the gene products of a family of small inducible genes (SIG), LD78, TCA3, IP10, 3-10C, 9E3/pCEF4, and gro/MGSA, and to several of the proteins secreted from platelet alpha-granules. Members of the SIG family have spatially conserved cysteine residues that vary in distance by only one amino acid residue as well as conserved proline residues at analogous sites. Hydrophilicity plots show alternating hydrophobic and hydrophilic domains which are similar for all members of the SIG family except IP10 and platelet factor 4, which show similarities to each other. The genomic organization of SIG family members is similar in the location of the splice junctions and the number of introns and exons, suggesting that they were derived from a common ancestor. The collective evidence suggests that a family of inducible cytokines, which are mitogenic or chemotactic, may act as intercellular coordinators of diverse responses designed to combat infection and promote the healing and regeneration of injured tissue.

Amino Acid Sequence↗
PubMed2026

Livestock Multi-Omics Integration: A Systematic Framework From Statistical Association to Causal Interpretation.

Livestock multi-omics integration is key to unraveling complex trait regulation, yet systematic, livestock-specific strategies remain scarce. This review traces the progression from single-omics accumulation to multi-dimensional integration, highlighting how large-scale genomic, epigenomic, and transcriptomic projects lay the foundation for functional dissection. We identify core impediments: extreme species diversity, marked data heterogeneity, limited sample sizes, and a pervasive reduction of multi-omics data to simplistic differential screens, resulting in low translational efficiency. We critically appraise four common pitfalls-overinterpreting correlation as causation, relegating proteomics to corroborating transcriptomics, incomplete microbiome-host integration lacking environmental context, and systematic neglect of metabolic fluxomics-and show how exposomics and fluxomics add necessary causal and dynamic dimensions. To address these, we propose a livestock-adapted three-tier analytical framework: (1) statistical association of cross-omics covariation patterns; (2) machine learning-driven feature mining and integrative modeling; and (3) causal interpretation encompassing Mendelian randomization, prior-knowledge-guided network inference, and physical causal evidence via fluxomics and metabolic control analysis. We further discuss how multimodal sequencing (single-cell, spatial, temporal) and generative AI can fundamentally mitigate heterogeneity and strengthen causal evidence. Finally, we outline future priorities in database standardization, livestock-specific benchmarking, and translational pipelines, charting a path from correlation-centric reporting to mechanistic causality and precision breeding.

Animals↗
PubMed2006

Changes in host chitinase isoforms in relation to wounding and colonization by Heterobasidion annosum: early and strong defense response in 33-year-old resistant Norway spruce clone.

We studied the defense reactions of 33-year-old susceptible and resistant clones of Norway spruce (Picea abies (L.) Karst.) to the major root-rot fungus Heterobasidion annosum (Fr.) Bref. and determined if tissue cultures can be used as a model system for studying defense responses of mature trees at the molecular level. Quantitative PCR analysis of genomic DNA obtained from samples taken at different times along the lesion length in living bark indicated that the fungus was present in higher amounts and extended further into the host tissue in the susceptible clone than in the resistant clone. In protein extracts from the same lesion samples, there were differences in temporal and spatial changes in host chitinase isoform profiles between the resistant and susceptible clones. Host chitinase isoforms with pI values approximately 4.8, 4.4 and 3.7 increased more during the first 7 days after wounding and inoculation and extended further along the lesion length in the resistant clone than in the susceptible clone. These results suggest that the time from wounding and infection to induction of defense-related expression is shorter in the resistant clone indicating a more efficient host defense response than in the susceptible clone. Tissue cultures from the same clones were not resistant to H. annosum and showed no difference in the timing of the increase in chitinase isoforms in response to the pathogen. However, tissue cultures from both clones showed an increase in chitinase isoforms within 6 to 24 h past inoculation, indicating that increased chitinase expression in response to the pathogen is part of a general defense response common to both mature clones and tissue cultures.

Basidiomycota↗
PubMed2003

Tracking a genetic signal of extinction-recolonization events in a neotropical tree species: Vouacapoua americana Aublet in French Guiana.

Drier periods from the late Pleistocene and early Holocene have been hypothesized to have caused the disappearance of various rainforest species over large geographical areas in South America and restricted the extant populations to mesic sites. Subsequent improvement in climatic conditions has been associated with recolonization. Changes in population size associated with these extinction-recolonization events should have affected genetic diversity within species. However, these historical hypotheses and their genetic consequences have rarely been tested in South America. Here, we examine the diversity of the chloroplast and nuclear genomes in a Neotropical rainforest tree species, Vouacapoua americana (Leguminosae, Caesalpinioideae) in French Guiana. The chloroplast diversity was analyzed using a polymerase chain reaction-restriction fragment length polymorphism method (six pairs of primers) in 29 populations distributed over most of French Guiana, and a subset of 17 populations was also analyzed at nine polymorphic microsatellite loci. To determine whether this species has experienced extinction-recolonization, we sampled populations in areas supposedly not or only slightly affected by climatic changes, where the populations would not have experienced frequent extinction, and in areas that appear to have been recently recolonized. In the putatively recolonized areas, we found patches of several thousands of hectares homogeneous for chloroplast variation that can be interpreted as the effect of recolonization processes from several geographical origins. In addition, we observed that, for both chloroplast and nuclear genomes, the populations in newly recolonized areas exhibited a significantly smaller allelic richness than others. Controlling for geographic distance, we also detected a significant correlation between chloroplast and nuclear population differentiation. This result indicates a cytonuclear disequilibrium that can be interpreted as a historical signal of a genetic divergence between fragmented populations. In conclusion, the spatial genetic structure of contemporary V. americana populations shows evidence that this species has experienced large extinction-recolonization events, which were possibly caused by past climatic change.

Climate↗