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At least 19 recordsLinked to original sources
PubMed1979

Genetic control of immunoregulatory circuits. Genes linked to the Ig locus govern communication between regulatory T-cell sets.

Antigen-stimulated Ly1:Qa1+ cells induce a nonimmune set of T-acceptor cells (surface phenotype Ly123+Qa1+) to participate in the generation of specific suppressive activity. The experiments reported here were designed to test the possibility that the interaction between T-inducer and T-acceptor cells might be governed by genes linked to the Ig locus. We find that inducer:acceptor interactions occur only if the inducer and acceptor T-cell sets are obtained from donor that are identical at the Ig locus and are independent of the Ig locus expressed on the B cells used for assay of T-helper activity. In addition, experiments using inducer and acceptor T cells from the congenic recombinant BAB. 14 strain show that T-T interactions are not governed by Ig-CH genes, per se. These data indicate that T-inducer: T-acceptor interactions are governed by Ig-linked genes that may control expression of VH-like structures on T cells, or control expression of as yet unidentified cell-surface molecules.

Animals↗
PubMed2026

Coarse-grained resource allocation modeling for decoding and rewiring microbial metabolism.

Microbial metabolism is a complex, emergent system driven by the coordinated interplay of intricate and dynamic molecular processes. To elucidate cellular behavior and enable biotechnological applications, quantitative models that address the inherent complexity of metabolism have been developed from a resource allocation perspective. Here, we synthesize recent advances in coarse-grained resource allocation frameworks and their applications in understanding microbial physiology and guiding gene circuit design. These frameworks reveal global regulatory constraints and predict cellular adaptation to nutrient and environmental changes. In addition, they enable the quantification of metabolic costs, the dissection of circuit-host interactions, and the development of strategies for burden mitigation. Collectively, these modeling frameworks provide a powerful platform for uncovering quantitative principles of microbial growth and engineering robust synthetic biological systems.

coarse-grained modeling↗
PubMed2025

Programmable promoter editing for precise control of transgene expression.

Subtle changes in gene expression direct cells to distinct cellular states. Identifying and controlling dose-dependent transgenes require tools for precisely titrating expression. Here, we develop a highly modular, extensible framework called DIAL for building editable promoters that allow for fine-scale, heritable changes in transgene expression. Using DIAL, we increase expression by recombinase-mediated excision of spacers between the binding sites of a synthetic zinc finger transcription factor and the core promoter. By nesting varying numbers and lengths of spacers, DIAL generates a tunable range of unimodal setpoints from a single promoter. Through small-molecule control of transcription factors and recombinases, DIAL supports temporally defined, user-guided control of transgene expression that is extensible to additional transcription factors. Lentiviral delivery of DIAL generates multiple setpoints in primary cells and induced pluripotent stem cells. As promoter editing generates stable states, DIAL setpoints are heritable, facilitating mapping of transgene levels to phenotype and fate in direct conversion to induced motor neurons. The DIAL framework opens opportunities for tailoring transgene expression and improving the predictability and performance of gene circuits across diverse applications.

Promoter Regions, Genetic↗
PubMed2026

Recent advances in molecular mechanisms to improve the efficacy of CAR-T cell therapy for viral diseases, cancer, and autoimmune diseases.

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies, yet its broader application to solid tumors, chronic viral infections, and autoimmune diseases remains constrained by antigen heterogeneity, immunosuppressive tissue microenvironments, T-cell exhaustion, limited persistence, and treatment-associated toxicities. These challenges have shifted the field from optimizing individual receptor constructs toward engineering CAR-T cells as programmable immune systems capable of adapting to diverse disease contexts. This review synthesizes recent advances in molecular engineering strategies that enhance CAR-T cell function beyond conventional receptor design. We discuss how receptor engineering, genome editing, transcriptional and epigenetic regulation, metabolic reprogramming, synthetic gene circuits, and safety-control platforms collectively reshape CAR-T cell fate, persistence, and therapeutic efficacy. Rather than functioning independently, these engineering strategies are increasingly integrated to generate context-specific cellular therapies capable of adapting to diverse disease environments, including cancer, autoimmune diseases, and chronic viral infections. We also highlight the potential for translation into clinical practice or clinical translation and discuss the major challenges associated with clinical implementation. Next-generation CAR-T therapies will increasingly integrate molecular engineering strategies or will rely on molecular engineering strategies to integrate antigen recognition, cellular fitness, immune regulation, and longevity rather than simply maximizing cytotoxic activity. Recent advances in programmable cellular engineering coupled with rigorous clinical evaluation as well as scalable manufacturing technologies or scalable manufacturing platforms in the treatment of other diseases beyond oncology will facilitate the development of safer, more durable, and broadly applicable cellular therapies.

Humans↗
PubMed2026

Glucose-responsive probiotics for glycaemic modulation in mice and monkeys.

Sustained and controlled delivery of glucose-lowering agents using engineered designer cells is recognized as an effective strategy for diabetes therapy1. However, current technologies rely on external signal control or have been programmed into mammalian cells using synthetic gene networks, which pose safety concerns arising from transplantation2,3. Here we developed an engineered oral-deliverable glucose-sensing and functional response probiotic living drug for 'sense-and-respond'-based control of diabetic blood glucose. We created a glucose sensor based on a synthetic gene circuit that incorporates the glucose-responsive transcriptional regulator HexR, coupled with a synthetic promoter. Upon oral administration of the engineered probiotics carrying the sensor, the cells reside temporarily in the intestine and regulate the expression of therapeutic transgenes in response to glucose levels that exceed the normal threshold. We show efficacy from the engineered probiotics for glycaemic control in multiple diabetic mouse and non-human primate models, demonstrating that long-term oral administration drives clear improvements in lipid profiles, while also attenuating development of multiple diabetic complications. Our probiotics-based living drug enables therapeutic dosing in response to real-time blood glucose levels, providing a programmable, orally deliverable sense-and-respond platform for metabolic therapy without transplantation.

Animals↗
PubMed2026

Hormone priming and metabolic engineering of phytohormone crosstalk in rice under combined biotic and abiotic stresses: a multi-omics perspective for climate-resilient crop development.

Rice (Oryza sativa L.) is the caloric backbone for more than half of humanity, yet it remains one of the most vulnerable crops to the simultaneous biotic and abiotic stresses exacerbated by climate change. Phytohormone priming and the complex crosstalk networks governed by transcription factor hubs like WRKY, MYB, and NAC serve as the central adaptive mechanism for stress resilience. This review synthesizes how multi-omics integration, including spatial and single-cell transcriptomics, is resolving the molecular architecture of hormonal priming and epigenetic stress memory. We critically evaluate advanced metabolic engineering and genome-editing strategies such as CRISPR-Cas9, base/prime editing, and synthetic gene circuits that enable precision modifications to decouple stress tolerance from historical yield penalties. Furthermore, we discuss the emerging roles of microbiome-assisted priming via synthetic consortia and the application of artificial intelligence and digital twins (continuously updated computational models of crop physiology) for predictive stress management. By integrating these diverse technological pillars, we propose a systems-level roadmap for developing climate-resilient rice cultivars capable of maintaining yield stability across a volatile combinatorial stress landscape. This synthesis provides a framework for translating mechanistic hormonal insights into field-applicable cultivars to ensure global food security.

CRISPR↗
PubMed2026

A voyage of reprogrammable metabolic bioengineering reshapes plant defense: from editing tools to synthetic systems.

Metabolic bioengineering has emerged as a transformative approach for reshaping plant defense by targeting intrinsic biosynthetic pathways to enhance immunity in modern agriculture. Moving beyond proof-of-concept metabolomics to broad-spectrum programmable pathway engineering addresses gaps in plant rational design and optimizes resilience in response to diverse environmental cues. This review aims to comprehensively highlight the transition of innovative approaches to phenolics, alkaloids, flavonoids, terpenoids, and benzoxazinoids, inferring adaptive reprogramming that mediates the growth-defense balance and functions as molecular sentinels in plants. Furthermore, decoding the volatile metabolome reveals a dynamic signaling interface that influences defense responses and stress-induced plant-microbe interactions, with the shikimate, jasmonate, and salicylate pathways functioning as central hubs for microbial deterrence and priming immune memory. Recent developments in multi-scalar genome-editing strategies, including CRISPR-driven combinatorial edits, enzyme orthogonalization, fluxomics, and spatially resolved multi-omics, reconfigure central and specialized metabolic fluxes toward improved defense function and regulation. Additionally, emerging tools, such as WUSCHEL2 and BABY BOOM transcriptional modules, and artificial engineering strategies integrating deep learning model-driven predictions facilitate rapid development of synthetic genetic circuits and support a predictive engineering of plants. Moreover, Mass spectrometry imaging (MSI) in spatial metabolomics enables to obtain structures and locations of unidentified endogenous metabolites within cells and tissues. Overall, this review emphasizes a diverse array of primary and secondary metabolites, spanning molecular concepts to recent advances in plant immune mechanisms. It also illustrates new frontiers in programmable metabolic engineering that accelerate the understanding of plant-microbe-metabolite cross-talks, offering strategies to improve plant resistance and advance sustainable agricultural solutions.

metabolic bioengineering↗
PubMed2025

Tunable, proteolytic dosage control of CRISPR-Cas systems enables precise gene therapy for dosage sensitive disorders.

The ability to modulate gene expression through modular and universal genetic tools like CRISPR-Cas has greatly advanced gene therapy for therapeutics and basic science. Yet, the inherent stochasticity of delivery methods cause variation in target gene expression at the single-cell level, limiting their applicability in systems that require more precise expression. Thus, we implement a modular incoherent feedforward loop based on proteolytic cleavage of Cas to reduce gene expression variability against the variability of vector delivery. We target a genome-integrated marker and demonstrate dosage control of gene activation and repression, post-delivery tuning, and RNA-based compatibility of the system. To illustrate therapeutic relevance, we target the gene RAI1, the haploinsufficiency and triplosensitivity of which cause two autism-related syndromes. We demonstrate dosage-controlled gene activation for both human and mouse Rai1 via viral delivery to patient-derived cell lines and mouse cortical neurons. Overall, we established a robust dosage control circuit for uniform gene expression, beneficial for basic and translational research.

Journal Article↗
PubMed2025

Gene regulation technologies for gene and cell therapy.

Gene therapy stands at the forefront of medical innovation, offering unique potential to treat the underlying causes of genetic disorders and broadly enable regenerative medicine. However, unregulated production of therapeutic genes can lead to decreased clinical utility due to various complications. Thus, many technologies for controlled gene expression are under development, including regulated transgenes, modulation of endogenous genes to leverage native biological regulation, mapping and repurposing of transcriptional regulatory networks, and engineered systems that dynamically react to cell state changes. Transformative therapies enabled by advances in tissue-specific promoters, inducible systems, and targeted delivery have already entered clinical testing and demonstrated significantly improved specificity and efficacy. This review highlights next-generation technologies under development to expand the reach of gene therapies by enabling precise modulation of gene expression. These technologies, including epigenome editing, antisense oligonucleotides, RNA editing, transcription factor-mediated reprogramming, and synthetic genetic circuits, have the potential to provide powerful control over cellular functions. Despite these remarkable achievements, challenges remain in optimizing delivery, minimizing off-target effects, and addressing regulatory hurdles. However, the ongoing integration of biological insights with engineering innovations promises to expand the potential for gene therapy, offering hope for treating not only rare genetic disorders but also complex multifactorial diseases.

Humans↗
PubMed2025

Innate immune molecular landscape following controlled human influenza virus infection.

Viral infections can induce prolonged changes in innate immunity. Here, we use blood samples from a human influenza H3N2 challenge study (NCT03883113) to perform comprehensive multi-omics analyses. We detect remodeling of immune programs in circulating innate immune cells that persist after resolution of the infection. We find changes associated with suppressed inflammation, including decreased cytokine and AP-1 gene expression as well as decreased accessibility at AP-1 targets and interleukin-related gene promoter regions. We also find decreased histone deacetylase gene expression, increased MAP kinase gene expression, and increased accessibility at interferon-related gene promoter regions. Genes involved in inflammation and methylation remodeling show modulation of gene-chromatin site regulatory circuit activity. These results reveal a coordinated rewiring of the molecular landscape in innate immune cells induced by mild influenza virus infection.

Humans↗
PubMed2024

Multi-organ gene expression analysis and network modeling reveal regulatory control cascades during the development of hypertension in female spontaneously hypertensive rat.

Hypertension is a multifactorial disease with stage-specific gene expression changes occurring in multiple organs over time. The temporal sequence and the extent of gene regulatory network changes occurring across organs during the development of hypertension remain unresolved. In this study, female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats were used to analyze expression patterns of 96 genes spanning inflammatory, metabolic, sympathetic, fibrotic, and renin-angiotensin (RAS) pathways in five organs, at five time points from the onset to established hypertension. We analyzed this multi-dimensional dataset containing ~15,000 data points and developed a data-driven dynamic network model that accounts for gene regulatory influences within and across visceral organs and multiple brainstem autonomic control regions. We integrated the data from female SHR and WKY with published multiorgan gene expression data from male SHR and WKY. In female SHR, catecholaminergic processes in the adrenal gland showed the earliest gene expression changes prior to inflammation-related gene expression changes in the kidney and liver. Hypertension pathogenesis in male SHR instead manifested early as catecholaminergic gene expression changes in brainstem and kidney, followed by an upregulation of inflammation-related genes in liver. RAS-related gene expression from the kidney-liver-lung axis was downregulated and intra-adrenal RAS was upregulated in female SHR, whereas the opposite pattern of gene regulation was observed in male SHR. We identified disease-specific and sex-specific differences in regulatory interactions within and across organs. The inferred multi-organ network model suggests a diminished influence of central autonomic neural circuits over multi-organ gene expression changes in female SHR. Our results point to the gene regulatory influence of the adrenal gland on spleen in female SHR, as compared to brainstem influence on kidney in male SHR. Our integrated molecular profiling and network modeling identified a stage-specific, sex-dependent, multi-organ cascade of gene regulation during the development of hypertension.

Animals↗
PubMed2025

Lentiviral CRISPRa/i in the adult prairie vole brain: modulating neuronal gene expression without DNA cleavage.

Prairie voles (Microtus ochrogaster) are a powerful model for studying the neurobiology of social bonding, yet tools for region- and cell type-specific gene regulation remain underdeveloped in this species. Here, we present a lentivirus-mediated CRISPR activation and interference (CRISPRa/i) platform for somatic gene modulation in the prairie vole brain. This system enables non-mutagenic, titratable regulation of gene expression in the adult brain without germline modification. Our dual-vector system includes one construct expressing dCas9-VPR (VP64-p65-Rta) referred to as CRISPRa or dCas9-KRAB-MeCP2 (Kruppel-associated box-methyl CpG binding protein 2), referred to as CRISPRi under a neuron-specific promoter, and a second construct delivering a U6-driven sgRNA (single guide RNA) alongside an elongation factor 1 alpha (EF1α)-driven mCherry reporter. We detail the design, production, and stereotaxic delivery of these tools and demonstrate their application by targeting four genes implicated in social behavior (Oxtr, Avpr1a, Drd1, and Drd2) across two mesolimbic brain regions: the nucleus accumbens and ventral pallidum. Gene expression analyses confirmed robust, bidirectional transcriptional modulation for selected targets, establishing a proof of concept for CRISPRa/i in this non-traditional model. The dual-vector design is readily adaptable to other gene targets, cell types, and brain regions, and can be multiplexed to provide a flexible and scalable framework for investigating gene function in behaviorally relevant circuits. These advances represent the first successful implementation of somatic CRISPRa/i in prairie voles and expand the genetic toolkit available for this species.

Avpr1a↗
PubMed2026

Systematic discovery of retina-enriched Rik genes identifies 1190005I06Rik as a novel modulator of visual signalling.

BACKGROUND: High‑throughput transcriptome projects have revealed thousands of mammalian genes with little or no functional annotation. Among these are hundreds of loci assigned provisional “Rik” identifiers following discovery in the RIKEN cDNA annotation effort. Although often dismissed as genomic dark matter, such genes may encode tissue‑restricted proteins that modulate physiologic functions and influence disease. The retina is a highly specialised neural tissue and a common site of inherited disorders; understanding its molecular repertoire could illuminate novel therapeutic avenues. METHODS: We integrated bulk RNA‑seq from ten adult mouse tissues, evolutionary and domain analysis, single‑cell RNA‑seq, and CRISPR/Cas9 gene disruption to systematically catalogue protein‑coding Rik genes enriched in the retina and test the function of a representative gene. RESULTS: A rigorous differential expression analysis identified 44 Rik genes with robust retina‑specific expression compared with nine non‑retinal tissues. Many of these genes lack orthologues beyond rodents, while others show broad conservation, illustrating a continuum from lineage‑restricted to conserved retinopathy candidates. Single‑cell transcriptomics revealed that these genes are expressed across retinal cell types, with the highest aggregate expression in cone photoreceptors and inner interneurons. To evaluate physiological significance, we generated a 1190005I06Rik knockout mouse. Although retinal architecture appeared normal, loss of 1190005I06Rik enhanced electroretinogram b‑wave amplitudes and altered light‑avoidance behaviour, indicating that this previously uncharacterised gene acts as a negative modulator of visual signalling. CONCLUSIONS: We present a curated atlas of retina‑enriched Rik genes and demonstrate that 1190005I06RIK modulates retinal circuit function. This resource expands the molecular landscape of the retina and provides new candidates for the genetic basis of inherited retinal disease. Our findings underscore that unannotated genes may exert measurable effects on sensory processing and warrant systematic exploration in the context of human ocular disorders.

Animals↗
PubMed2025

Profiling hippocampal neuronal populations reveals unique gene expression mosaics reflective of connectivity-based degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.

INTRODUCTION: Individuals with Down syndrome (DS) exhibit neurological deficits throughout life including the development of in Alzheimer's disease (AD) pathology and cognitive impairment. At the cellular level, dysregulation in neuronal gene expression is observed in postmortem human brain and mouse models of DS/AD. To date, RNA-sequencing (RNA-seq) analysis of hippocampal neuronal gene expression including the characterization of discrete circuit-based connectivity in DS remains a major knowledge gap. We postulate that spatially characterized hippocampal neurons display unique gene expression patterns due, in part, to dysfunction of the integrity of intrinsic circuitry. METHODS: We combined laser capture microdissection to microisolate individual neuron populations with single population RNA-seq analysis to determine gene expression analysis of CA1 and CA3 pyramidal neurons and dentate gyrus granule cells located in the hippocampus, a region critical for learning, memory, and synaptic activity. RESULTS: The hippocampus exhibits age-dependent neurodegeneration beginning at ~6 months of age in the Ts65Dn mouse model of DS/AD. Each population of excitatory hippocampal neurons exhibited unique gene expression alterations in Ts65Dn mice. Bioinformatic inquiry revealed unique vulnerabilities and differences with mechanistic implications coinciding with onset of degeneration in this model of DS/AD. CONCLUSIONS: These cell-type specific vulnerabilities may underlie degenerative endophenotypes suggesting precision medicine targeting of individual populations of neurons for rational therapeutic development.

Alzheimer’s disease↗
PubMed2026

Developmental patterning of adipose tissue by abd-A and Abd-B homeotic genes in Drosophila melanogaster.

The Bithorax Complex (BX-C) homeobox proteins specify segmental identities along the anterior-posterior axis during Drosophila embryogenesis. Differential expression of the BX-C genes abd-A and Abd-B distinguishes abdominal from thoracic adipocytes, yet the mechanism regulating this heterogeneity remains poorly understood. Here, we identify cis-regulatory elements (CREs) and transcription factors that direct abdominal-specific expression of abd-A and Abd-B in the larval fat body. Fine-mapping analyses identified a 627-bp CRE within the Abd-B locus and a ~6-kb CRE within the abd-A locus sufficient to drive heterogeneous expression. Yeast one-hybrid screening combined with functional analyses identified Lola, Lolal, and Combgap as key repressors of Abd-B, whereas Piragua (Prg) and Seven up (Svp) function as transcriptional activators, indicating that adipocyte heterogeneity in postembryonic adipose tissue is actively regulated. In turn, lola and prg are repressed by Abd-B, whereas lolal and svp are activated, forming a feedback circuit further modulated by Wnt signaling, which promotes lola and lolal expression while repressing svp. CUT&RUN analyses suggest that these interactions are direct, with dTCF/Pan and Abd-B occupancy detected at target loci. Together, our findings define a transcriptional circuit that regulates Abd-B gene transcription to pattern adipose tissue and may establish the developmental basis of fat depot specialization.

Abd-B↗
PubMed2026

Local gene editing of fibroblasts in tumors reveals a new cancer-associated fibroblast state.

Fibroblasts play critical roles in regulating cellular relationships during tissue homeostasis, immunity, and tumor biology at multiple sites. However, tools to perturb fibroblasts at just one site in vivo are limited, restricting our understanding of how these cellular relationships act locally. We optimized local gene editing of fibroblasts in mouse tumor models to investigate how fibroblast perturbations affect the tumor microenvironment (TME). By knocking out receptors Osmr, Tgfbr2, or Il1r1 on cancer-associated fibroblasts (CAFs), we uncover that TGFBR2 signaling loss induces the emergence of a new Col18a1hi CAF cell state that is associated with worse survival in pancreatic cancer patients. Combinatorial gene KOs in CAFs reveals a circuit where these Col18a1hi CAFs reshape the TME by recruiting Siglec-Fhi neutrophils via Cxcl5 expression, and where this Col18a1hi CAF cell state is dependent on TNFR1 and canonical Wnt signaling. Together, a fast, affordable, and modular engineering method is demonstrated, allowing discovery of modified fibroblast identities and local intercellular relationships in the TME.

Animals↗
PubMed1978

Isolation and characterization of flightless mutants in Drosophila melanogaster.

Since animal behaviour is executed through neuronal circuits including sensory receptors and muscle, genes vital for their development and differentiation must be found among mutants having behavioural anomaly. After mutagenesis with ethyl methanesulphonate (EMS), we screened for X-linked flightless mutants of Drosophila melanogaster by using column-type flight tester. Approximately 10(4) individuals were screened and 21 mutant genes were isolated. Chromosomal mapping and complementation experiments revealed that they belong to 15 cistrons randomly located on X chromosome, three cistrons having more than two alleles. Two of the isolated mutants (fltO2 and fltH, which are recessive both behaviourally and morphologically) were analysed with the mosaic fate mapping technique, and both were found to have their primary foci in mesodermal region of blastoderm, suggesting that the genes exert their primary effect in indirect flight muscle. Electronmicroscopic studies on the muscles from four alleles of the fltO2 cistron revealed an abnormality in myofibrillar arrangement. A possible deficit within Z-band components is discussed in relation to wings-up B mutants. The indirect flight muscle of flltH was also examined, and it was found that sarcomere length and diameter of myofibrils were abnormal. It was postulated that a possible factor which controls size of myofibrils is defective in this mutant. These examples indicate the advantage of combining ultrastructural examination with genetic mosaic mapping technique.

Animals↗