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Publications in Biomedical Research by NOMIS researchers

Culture-independent meta-pangenomics enabled by long-read metagenomics reveals associations with pediatric undernutrition

NOMIS Researcher(s)

Published in

September 9, 2025

The human gut microbiome is linked to child malnutrition, yet traditional microbiome approaches lack resolution. We hypothesized that complete metagenome-assembled genomes (cMAGs), recovered through long-read (LR) DNA sequencing, would enable pangenome and microbial genome-wide association study (GWAS) analyses to identify microbial genetic associations with child linear growth. LR methods produced 44–64× more cMAGs per gigabase pair (Gbp) than short-read methods, with PacBio (PB) yielding the most accurate and cost-effective assemblies. In a Malawian longitudinal pediatric cohort, we generated 986 cMAGs (839 circular) from 47 samples and applied this database to an expanded set of 210 samples. Machine learning identified species predictive of linear growth. Pangenome analyses revealed microbial genetic associations with linear growth, while genome instability correlated with declining length-for-age Z score (LAZ). This resource demonstrates the power of comparing cMAGs with health trajectories and establishes a new standard for microbiome association studies.

Research field(s)
Bioinformatics, Microbiology, Pediatrics

DOI
10.1016/j.cell.2025.08.020

Targeted DNA ADP-ribosylation triggers templated repair in bacteria and base mutagenesis in eukaryotes

NOMIS Researcher(s)

Published in

September 4, 2025

Base editors create precise genomic edits by directing nucleobase deamination or removal without inducing double-stranded DNA breaks. However, a vast chemical space of other DNA modifications remains to be explored for genome editing. Here we harness the bacterial antiphage toxin DarT2 to append ADP-ribosyl moieties to DNA, unlocking distinct editing outcomes in bacteria versus eukaryotes. Fusing an attenuated DarT2 to a Cas9 nickase, we program site-specific ADP-ribosylation of thymines within a target DNA sequence. In tested bacteria, targeting drives homologous recombination, offering flexible and scar-free genome editing without base replacement or counterselection. In tested yeast, plant and human cells, targeting drives substitution of the modified thymine to adenine or a mixture of adenine and cytosine with limited insertions or deletions, offering edits inaccessible to current base editors. Altogether, our approach, called append editing, leverages the addition of chemical moieties to DNA to expand current modalities for precision gene editing.

Research field(s)
Biotechnology, Biochemistry & Molecular Biology, Genetics & Heredity, Microbiology

DOI
10.1038/s41587-025-02802-w

The actin cortex acts as a mechanical memory of morphology in confined migrating cells

NOMIS Researcher(s)

Published in

August 25, 2025

Cell migration in narrow microenvironments occurs in numerous physiological processes. It involves successive cycles of confinement and release that drive important morphological changes. However, it remains unclear whether migrating cells can retain a memory of their past morphological states that could potentially facilitate their navigation through confined spaces. We demonstrate that local geometry governs a switch between two cell morphologies, thereby facilitating cell passage through long and narrow gaps. We combined cell migration assays on standardized microsystems with biophysical modelling and biochemical perturbations to show that migrating cells have a long-term memory of past confinement events. The morphological cell states correlate across transitions through actin cortex remodelling. These findings indicate that mechanical memory in migrating cells plays an active role in their migratory potential in confined environments.

Research field(s)
Biomedical Engineering, Biochemistry & Molecular Biology, Biophysics

DOI
10.1038/s41567-025-02980-z

A male-essential miRNA is key for avian sex chromosome dosage compensation

NOMIS Researcher(s)

Published in

July 16, 2025

Birds have a sex chromosome system in which females are heterogametic (ZW) and males are homogametic (ZZ)1. The differentiation of avian sex chromosomes from ancestral autosomes entails the loss of most genes from the W chromosome during evolution1,2. However, the extent to which mechanisms evolved that counterbalance this substantial reduction in female gene dosage remains unclear. Here we report functional in vivo and evolutionary analyses of a Z-linked microRNA (miR-2954) with strong male-biased expression, previously proposed to mediate avian sex chromosome dosage compensation3. We knocked out miR-2954 in chicken, which resulted in early embryonic lethality in homozygous knockout males, probably driven by specific upregulation of dosage-sensitive Z-linked target genes. Evolutionary gene expression analyses further revealed that these dosage-sensitive target genes underwent both transcriptional and translational upregulation on the single Z in female birds. Altogether, this work unveils a scenario in which evolutionary pressures following W gene loss drove transcriptional and translational upregulation of dosage-sensitive Z-linked genes in females but also their transcriptional upregulation in males. The resulting excess of transcripts in males, resulting from the combined activity of two upregulated dosage-sensitive Z gene copies, was in turn offset by the emergence of a highly targeted miR-2954-mediated transcript degradation mechanism during avian evolution. This study uncovered a unique sex chromosome dosage compensation system in birds, in which a microRNA has become essential for male survival.

Research field(s)
Bioinformatics, Biochemistry & Molecular Biology, Developmental Biology, Genetics & Heredity, Evolutionary Biology

DOI
10.1038/s41586-025-09256-9

Atlas of amnion development during the first trimester of human pregnancy

NOMIS Researcher(s)

Published in

July 14, 2025

The amnion is a critical extra-embryonic structure that supports foetal development, yet its ontogeny remains poorly defined. Here, using single-cell transcriptomics, we identified major cell types and subtypes in the human amnion across the first trimester of pregnancy, broadly categorized into epithelial, mesenchymal and macrophage lineages. We uncovered epithelial–mesenchymal and epithelial–immune transitions, highlighting dynamic remodelling during early pregnancy. Our results further revealed key intercellular communication pathways, including BMP4 signalling from mesenchymal to epithelial cells and TGF-β signalling from macrophages to mesenchymal cells, suggesting coordinated interactions that drive amnion morphogenesis. In addition, integrative comparisons across humans, non-human primates and in vitro stem cell-based models reveal that stem cell-based models recapitulate various stages of amnion development, emphasizing the need for careful selection of model systems to accurately recapitulate in vivo amnion formation. Collectively, our findings provide a detailed view of amnion cellular composition and interactions, advancing our understanding of its developmental role and regenerative potential.

Research field(s)
Molecular Biology, Developmental Biology, Microbiology

DOI
10.1038/s41556-025-01696-9

SARS-CoV-2 nucleocapsid protein directly prevents cGAS–DNA recognition through competitive binding

NOMIS Researcher(s)

Published in

June 23, 2025
A hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the delayed interferon response. Interferons are typically produced upon host recognition of pathogen- or damage-associated molecular patterns, such as nucleic acids. While the mechanisms by which SARS-CoV-2 evades host recognition of its RNA are well studied, how it evades immune responses to cytosolic DNA—leaked from mitochondria or nuclei during infection—remains poorly understood. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein directly suppresses DNA sensing by cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS). Although primarily known for packaging the viral RNA genome, we uncover that the SARS-CoV-2 nucleocapsid protein also binds DNA with high affinity and competitively blocks cGAS activation. Using cell-free biochemical and biophysical approaches, including single-molecule optical tweezers, we show that the nucleocapsid protein binds to DNA at nanomolar concentrations and cocondenses with DNA at micromolar concentrations, thereby impeding stable cGAS-DNA interactions required for signal propagation. Hyperphosphorylation of the nucleocapsid protein diminishes its competitive binding capacity. Our findings reveal an unexpected role of the SARS-CoV-2 nucleocapsid protein in directly suppressing the cGAS-STING pathway, strongly suggesting that this contributes to the delayed interferon response during infection. This study raises the possibility that nucleocapsid proteins of other RNA viruses may also exhibit moonlighting functions by antagonizing host nucleic acid–sensing pathways.

Research field(s)
Biological Physics, Biochemistry & Molecular Biology, Virology, Immunology

DOI
10.1073/pnas.2426204122

Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates

NOMIS Researcher(s)

Published in

May 23, 2025

Cytosolic aggregation of the nuclear protein TAR DNA-binding protein 43 (TDP-43) is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43-enriched phase within stress granules, which subsequently transition into pathological aggregates. Intra-condensate demixing of TDP-43 is observed in iPS-motor neurons, a disease mouse model, and patient samples. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We suggest that up-concentration inside condensates followed by intra-condensate demixing could be a general pathway for protein aggregation.

Research field(s)
Neuroscience, Biochemistry & Molecular Biology, Biophysics

DOI
10.1016/j.cell.2025.04.039

Robust prediction of synthetic gRNA activity and cryptic DNA repair by disentangling cellular CRISPR cleavage outcomes

NOMIS Researcher(s)

Published in

May 21, 2025

The ability to robustly predict guide RNA (gRNA) activity is a long-standing goal for CRISPR applications, as it would reduce the need to pre-screen gRNAs. Quantification of formation of short insertions and deletions (indels) after DNA cleavage by transcribed gRNAs has been typically used to measure and predict gRNA activity. We evaluate the effect of chemically synthesized Cas9 gRNAs on different cellular DNA cleavage outcomes and find that the activity of different gRNAs is largely similar and often underestimated when only indels are scored. We provide a simple linear model that reliably predicts synthetic gRNA activity across cell lines, robustly identifies inefficient gRNAs across different published datasets, and is easily accessible via online genome browser tracks. In addition, we develop a homology-directed repair efficiency prediction tool and show that unintended large-scale repair events are common for Cas9 but not for Cas12a, which may be relevant for safety in gene therapy applications.

Research field(s)
Genetics & Heredity

DOI
10.1038/s41467-025-59947-0

Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS

NOMIS Researcher(s)

Published in

May 19, 2025

Mutations in FUS and TARDBP cause amyotrophic lateral sclerosis (ALS), but the precise mechanisms of selective motor neuron degeneration remain unresolved. To address if pathomechanisms are shared across mutations and related to either gain- or loss-of-function, we performed single-cell RNA sequencing across isogenic induced pluripotent stem cell-derived neuron types, harbouring FUS P525L, FUS R495X, TARDBP M337V mutations or FUS knockout. Transcriptional changes were far more pronounced in motor neurons than interneurons. About 20% of uniquely dysregulated motor neuron transcripts were shared across FUS mutations, half from gain-of-function. Most indicated mitochondrial impairments, with attenuated pathways shared with mutant TARDBP M337V as well as C9orf72-ALS patient motor neurons. Mitochondrial motility was impaired in ALS motor axons, even with nuclear localized FUS mutants, demonstrating shared toxic gain-of-function mechanisms across FUS- and TARDBP-ALS, uncoupled from protein mislocalization. These early mitochondrial dysfunctions unique to motor neurons may affect survival and represent therapeutic targets in ALS.

Research field(s)
Molecular Biology, Neuroscience, Biochemistry & Molecular Biology

DOI
10.1038/s41467-025-59679-1

Small-molecule dissolution of stress granules by redox modulation benefits ALS models

NOMIS Researcher(s)

Published in

May 14, 2025

Neurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.

Research field(s)
Neuroscience, Biochemistry & Molecular Biology

DOI
10.1038/s41589-025-01893-5

DNA binding and mitotic phosphorylation protect polyglutamine proteins from assembly formation

NOMIS Researcher(s)

Published in

April 15, 2025
Polyglutamine (polyQ) expansion is associated with pathogenic protein aggregation in neurodegenerative disorders. However, long polyQ tracts are also found in many transcription factors (TFs), such as FOXP2, a TF implicated in human speech. Here, we explore how FOXP2 and other glutamine-rich TFs avoid unscheduled assembly. Throughout interphase, DNA binding, irrespective of sequence specificity, has a solubilizing effect. During mitosis, multiple phosphorylation events promote FOXP2’s eviction from chromatin and supplant the solubilizing function of DNA. Further, human-specific amino acid substitutions linked to the evolution of speech map to a mitotic phospho-patch, the “EVO patch,” and reduce the propensity of the human FOXP2 to assemble. Fusing the pathogenic form of Huntingtin to either a DNA-binding domain, a phosphomimetic variant of this EVO patch, or a negatively charged peptide is sufficient to diminish assembly formation, suggesting that hijacking mechanisms governing solubility of glutamine-rich TFs may offer new strategies for treatment of polyQ expansion diseases.

Research field(s)
Neuroscience, Biochemistry & Molecular Biology, Genetics & Heredity, Evolutionary Biology

DOI
10.1016/j.cell.2025.03.031

Comprehensive interrogation of synthetic lethality in the DNA damage response

NOMIS Researcher(s)

Published in

April 9, 2025

The DNA damage response (DDR) is a multifaceted network of pathways that preserves genome stability1,2. Unravelling the complementary interplay between these pathways remains a challenge3,4. Here we used CRISPR interference (CRISPRi) screening to comprehensively map the genetic interactions required for survival during normal human cell homeostasis across all core DDR genes. We captured known interactions and discovered myriad new connections that are available online. We defined the molecular mechanism of two of the strongest interactions. First, we found that WDR48 works with USP1 to restrain PCNA degradation in FEN1/LIG1-deficient cells. Second, we found that SMARCAL1 and FANCM directly unwind TA-rich DNA cruciforms, preventing catastrophic chromosome breakage by the ERCC1–ERCC4 complex. Our data yield fundamental insights into genome maintenance, provide a springboard for mechanistic investigations into new connections between DDR factors and pinpoint synthetic vulnerabilities that could be exploited in cancer therapy.

Partnership(s)
,

Research field(s)
Bioinformatics, Biochemistry & Molecular Biology, Genetics & Heredity, Oncology & Carcinogenesis

DOI
10.1038/s41586-025-08815-4

BMP-dependent patterning of ectoderm tissue material properties modulates lateral mesendoderm cell migration during early zebrafish gastrulation

NOMIS Researcher(s)

Published in

March 8, 2025

Cell migration is a fundamental process during embryonic development. Most studies in vivo have focused on the migration of cells using the extracellular matrix (ECM) as their substrate for migration. In contrast, much less is known about how cells migrate on other cells, as found in early embryos when the ECM has not yet formed. Here, we show that lateral mesendoderm (LME) cells in the early zebrafish gastrula use the ectoderm as their substrate for migration. We show that the lateral ectoderm is permissive for the animal-pole-directed migration of LME cells, while the ectoderm at the animal pole halts it. These differences in permissiveness depend on the lateral ectoderm being more cohesive than the animal ectoderm, a property controlled by bone morphogenetic protein (BMP) signaling within the ectoderm. Collectively, these findings identify ectoderm tissue cohesion as one critical factor in regulating LME migration during zebrafish gastrulation.

Partnership(s)
,

Research field(s)
Molecular Biology, Biophysics

DOI
10.1016/j.celrep.2025.115387

AI-based approach to dissect the variability of mouse stem cell-derived embryo models

NOMIS Researcher(s)

Published in

February 19, 2025

Recent advances in stem cell-derived embryo models have transformed developmental biology, offering insights into embryogenesis without the constraints of natural embryos. However, variability in their development challenges research standardization. To address this, we use deep learning to enhance the reproducibility of selecting stem cell-derived embryo models. Through live imaging and AI-based models, we classify 900 mouse post-implantation stem cell-derived embryo-like structures (ETiX-embryos) into normal and abnormal categories. Our best-performing model achieves 88% accuracy at 90 h post-cell seeding and 65% accuracy at the initial cell-seeding stage, forecasting developmental trajectories. Our analysis reveals that normally developed ETiX-embryos have higher cell counts and distinct morphological features such as larger size and more compact shape. Perturbation experiments increasing initial cell numbers further supported this finding by improving normal development outcomes. This study demonstrates deep learning’s utility in improving embryo model selection and reveals critical features of ETiX-embryo self-organization, advancing consistency in this evolving field.

Research field(s)
Bioinformatics, Artificial Intelligence & Image Processing, Biophysics, Developmental Biology

DOI
10.1038/s41467-025-56908-5

Fluoxetine promotes IL-10–dependent metabolic defenses to protect from sepsis-induced lethality

NOMIS Researcher(s)

Published in

February 14, 2025

Selective serotonin reuptake inhibitors (SSRIs) are some of the most prescribed drugs in the world. While they are used for their ability to increase serotonergic signaling in the brain, SSRIs are also known to have a broad range of effects beyond the brain, including immune and metabolic effects. Recent studies have demonstrated that SSRIs are protective in animal models and humans against several infections, including sepsis and COVID-19; however, the mechanisms underlying this protection are largely unknown. Here, we mechanistically link two previously described effects of the SSRI fluoxetine in mediating protection against sepsis. We show that fluoxetine-mediated protection is independent of peripheral serotonin and instead increases levels of circulating interleukin-10 (IL-10). IL-10 is necessary for protection from sepsis-induced hypertriglyceridemia, preventing cardiac effects including impairment of glucose oxidation, ectopic lipid accumulation, ventricular stretch and possibly cardiac failure. Our work reveals a beneficial “off-target” effect of fluoxetine, and reveals a protective immunometabolic defense mechanism with therapeutic potential.

Partnership(s)
,

Research field(s)
Biochemistry & Molecular Biology, Immunology, Pharmacology & Pharmacy, Microbiology

DOI
10.1126/sciadv.adu4034

Resolving the three-dimensional interactome of human accelerated regions during human and chimpanzee neurodevelopment

NOMIS Researcher(s)

Published in

January 30, 2025

Human accelerated regions (HARs) have been implicated in human brain evolution. However, insight into the genes and pathways they control is lacking, hindering the understanding of their function. Here, we identify 2,963 conserved gene targets for 1,590 HARs and their orthologs in human and chimpanzee neural stem cells (NSCs). Conserved gene targets are enriched for neurodevelopmental functions and are overrepresented among differentially expressed genes (DEGs) identified in human NSCs (hNSCs) and chimpanzee NSCs (cNSCs) as well as in human versus non-human primate brains. Species-specific gene targets do not converge on any function and are not enriched among DEGs. HAR targets also show cell-type-specific expression in the human fetal brain, including in outer radial glia, which are linked to cortical expansion. Our findings support that HARs influence brain evolution by altering the expression of ancestral gene targets shared between human and chimpanzee rather than by gaining new targets in human and facilitate hypothesis-directed studies of HAR biology.

Research field(s)
Bioinformatics, Developmental Biology, Evolutionary Biology

DOI
10.1016/j.cell.2025.01.007

Bile acid synthesis impedes tumor-specific T cell responses during liver cancer

NOMIS Researcher(s)

Published in

January 9, 2025

The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid–CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy. Furthermore, different BAs regulated CD8+ T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.

Partnership(s)

Research field(s)
Biomedical Research, Biochemistry & Molecular Biology, Microbiology, Immunology, Oncology & Carcinogenesis

DOI
10.1126/science.adl4100

Alzheimer’s disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain

NOMIS Researcher(s)

Published in

December 19, 2024

INTRODUCTION: While there may be microbial contributions to Alzheimer’s disease (AD), findings have been inconclusive. We recently reported an AD-associated CD83(+)microglia subtype associated with increased immunoglobulinG4(IgG4) in the transverse colon (TC).

METHODS: We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association.

RESULTS: CD83(+) microglia in the superior frontal gyrus (SFG) are associated with elevated IgG4 and human cytomegalovirus (HCMV) in the TC, anti-HCMV IgG4 in cerebrospinal fluid, and both HCMV and IgG4 in the SFG and vagal nerve. This association was replicated in an independent AD cohort. HCMV-infected cerebral organoids showed accelerated AD pathophysiological features (Aβ42 and pTau-212) and neuronal death.

DISCUSSION: Findings indicate complex, cross-tissue interactions between HCMV and the adaptive immune response associated with CD83(+)microglia in persons with AD. This may indicate an opportunity for antiviral therapy in persons with AD and biomarker evidence of HCMV, IgG4, or CD83(+)microglia.

Research field(s)
Genetics & Heredity, Neurology & Neurosurgery, Biology

DOI
10.1002/alz.14401

Spatial transcriptomic clocks reveal cell proximity effects in brain ageing

NOMIS Researcher(s)

Published in

December 18, 2024

Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk1. Brain ageing is complex and is accompanied by many cellular changes2. Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions—exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types. Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell–cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.

Research field(s)
Bioinformatics, Biochemistry & Molecular Biology, Immunology, Neurology & Neurosurgery

DOI
10.1038/s41586-024-08334-8

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