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PubMed2025

GWAS for Periodontitis Phenotypes Using Multi-Ancestry All of Us Research Platform.

Periodontitis is a multifactorial inflammatory disease whose pathogenesis is associated with intricate interactions between genetic and environmental factors. Leveraging electronic health records data from the All of Us Research Program, we stratified periodontitis by clinically relevant dimensions: stage, grade, and extent. Based on these phenotypes, we performed a multi-ancestry genome-wide association study, focusing on predominant ancestry populations of African, European, and Admixed American. Our study cohort comprised 3,881 periodontitis patients and a control group of 10,760 patients with dental caries and without periodontitis. Ancestry-specific GWAS revealed significant genetic associations (P<5×10-8) in periodontitis grade phenotypes at the LINC00294 and CLMN loci in the African ancestry population and also confirmed via the multi-ancestry meta-analysis. In addition, the XYLT1 locus emerged as a significant signal associated with periodontitis grade phenotype in the admixed American GWAS. Our GWAS comparing periodontitis to dental caries in the admixed American population identified several significant loci, including RABGAP1L, previously linked to immune regulation, DCHS2, a cadherin-related gene involved in bone mineralization and tissue morphogenesis, and OSTM1, known to be crucial for bone remodeling. The findings of our study highlight the potential of integrating EHR and genomic data from large-scale biobanks to achieve informative dental phenotyping, uncover novel molecular insights into periodontal disease, and personalize treatment approaches.

Journal Article↗

PubMed2025

Multiple Psychiatric Traits Enriched for Brain Tissues in the Early Postpartum Period.

BACKGROUND: The perinatal period is a high-risk time for onset of various psychiatric disorders. However, it is unclear how genetic risk factors for these disorders interact with biological changes associated with pregnancy and postpartum. This study evaluates whether psychiatric genome-wide association study (GWAS) results are enriched within various brain regions across the perinatal period. METHODS: Tissue-specific enrichment analyses were conducted to estimate the potential impact of GWAS loci on transcriptional changes in the brain across the perinatal period. GWAS summary statistics were obtained for 26 psychiatric phenotypes. RNA-sequencing data was acquired from four brain regions (hypothalamus, hippocampus, cerebellum, and neocortex) in mice at six timepoints (virgin, 14- and 16-days post-conception, and 1-, 3- and 10-days postpartum). RESULTS: Hippocampus and neocortex in the early postpartum period are significantly enriched (q-value < 0.05) for genetic variants associated with schizophrenia (SCZ), bipolar disorder (BD), depressive symptoms, and major depressive disorder with suicidal features. The most significant enrichment occurred in the neocortex for SCZ and BD, peaking at postpartum day 1 (SCZ p-value = 3.85 × 10-8; BD p-value = 6.65 × 10-5). In the hippocampus, BD and SCZ were enriched at postpartum day 1 (SCZ p-value = 3.27 × 10-3; BD p-value = 4.33 × 10-3). No enrichment was observed in cerebellum or hypothalamus for any of the psychiatric traits tested. CONCLUSIONS: The results accord with previous epidemiological studies and provide context in which to interpret GWAS results. Understanding the burden of genetic variants across the perinatal period may help prioritise pathways underlying onset of psychiatric disorders outside of pregnancy and postpartum periods.

Journal Article↗

PubMed2025

A bacterial PrimPol-reverse transcriptase hybrid protein has a proofreading exonuclease activity that can be transferred to other reverse transcriptases.

Gene disruption analysis revealed that an E. coli PPRT protein, which has an N-terminal Primase-Polymerase (PrimPol) domain fused to a group II intron-like reverse transcriptase (RT) domain followed by a long C-terminal domain (CTD), contributes to a cellular oxidative DNA damage response in addition to its previously described function in phage defense. Biochemical analysis showed that the PrimPol domain has an error-prone DNA polymerase activity that enables read through of oxidation-induced DNA damage. Surprisingly, we found that the RT-like domain, in addition to synthesizing protein-primed DNAs for phage defense, has a 3' to 5' DNA exonuclease activity that functions in proofreading DNAs synthesized by the PrimPol domain. Extending these findings, we identified structural features that contribute to this proofreading activity, enabling us to associate it with both a group II intron-encoded and retroviral RT and suggesting general methods for incorporating proofreading activity into RTs.

DNA sequencing↗

PubMed2025

Identification of Sample Processing Errors in Microbiome Studies Using Host Genetic Profiles.

In microbiome studies, sample processing errors are frequent and difficult to detect, especially in large studies involving multiple sites, personnel, and sample types. We present two complementary approaches to identify such errors using host DNA profiled via metagenomic sequencing of microbiome samples. The first approach compares host SNPs inferred from metagenomics to independently obtained genotypes (e.g., microarray genotypes) to match samples to their donors, while the second method compares metagenomics-inferred SNPs between samples to identify samples supplied by the same donor. Furthermore, we demonstrate that combining these methods with experimental metadata provides greater confidence in the identification of errors. Analyzing a longitudinal vaginal microbiome dataset, we demonstrate the ability of our approach to identify mislabeled samples. Using subsampling, we further show that our methods are robust to low sequencing coverage. Overall, our analysis highlights the frequency of processing errors in microbiome studies. We therefore recommend applying error-detection methods in all studies with suitable data.

Journal Article↗

PubMed2025

A Modular Platform for the Optogenetic Control of Small GTPase Activity in Living Cells Reveals Long-Range RhoA Signaling.

Small GTPases are critical regulators of cellular processes, such as cell migration, and comprise a family of over 167 proteins in the human genome. Importantly, the location-dependent regulation of small GTPase activity is integral to coordinating cellular signaling. Currently, there are no generalizable methods for directly controlling the activity of these signaling enzymes with subcellular precision. To address this issue, we introduce a modular, optogenetic platform for the spatial control of small GTPase activity within living cells, termed spLIT-small GTPases. This platform enabled spatially precise control of cytoskeletal dynamics such as filopodia formation (spLIT-Cdc42) and directed cell migration (spLIT-Rac1). Furthermore, a spLIT-RhoA system uncovered previously unreported long-range RhoA signaling in HeLa cells, resulting in bipolar membrane retraction. These results establish spLIT-small GTPases as a versatile platform for the direct, spatial control of small GTPase signaling and demonstrate the ability to uncover spatially defined aspects of small GTPase signaling.

Journal Article↗

PubMed2025

Cumulative Genetic Risk for Asthma Contributes to Disease Severity in Children with Asthma living in Urban Environments.

BACKGROUND: Childhood-onset asthma is highly heritable, with nearly 200 risk loci identified in genome-wide association studies. Aggregated polygenic risk scores can be used to quantify genetic predisposition to asthma, but their power to predict asthma severity in multi-ancestral groups has not been determined. OBJECTIVE: Our aim was to examine the predictive power of biobank-derived asthma polygenic risk scores in children with asthma living in urban environments. METHODS: We generated polygenic risk scores for asthma, derived from a large-scale genome-wide association meta-analysis, in four multi-ancestry asthma study cohorts of children living in urban environments. We assessed genetic predictions across different subphenotypes of asthma and tested for associations between genetic asthma risk and measures of asthma severity. RESULTS: Genetic asthma prediction was significantly stronger for more symptomatic asthma phenotypes (P<0.001). Polygenic risk scores were significantly higher in difficult-to-control vs. easy-to-control asthma (P=0.02). Genetic risk was also significantly associated with more frequent exacerbations (P=0.03), higher blood eosinophil levels (P=0.01), and lower lung function (P<0.001). CONCLUSION: Cumulative genetic risk for asthma is associated with disease severity and exacerbation risk in children with asthma living in urban environments.

Journal Article↗

PubMed2025

Gene model for the ortholog of foxo in Drosophila sechellia.

Gene model for the ortholog of forkhead box, sub-group O (foxo) in the May 2011 (Broad dsec_caf1/DsecCAF1) Genome Assembly (GenBank Accession: GCA_000005215.1) of Drosophila sechellia. This ortholog was characterized as part of a developing dataset to study the evolution of the Insulin/insulin-like growth factor signaling pathway (IIS) across the genus Drosophila using the Genomics Education Partnership gene annotation protocol for Course-based Undergraduate Research Experiences.

Bioinformatics↗

PubMed2025

Phasing single-molecule nano-NOMe-seq reveals chromatin state heterogeneity in the context of transcription and long-range interactions.

A central challenge in molecular biology is determining how 3D chromatin architecture, particularly enhancer-promoter looping and insulating CTCF-mediated interactions, influences gene transcription in individual cells, which has significant implications for healthy and diseased states. To overcome current limitations in imaging and genomic technologies, we developed a cluster-based phasing strategy using long read nano-NOMe-seq to link distinct CTCF binding states-captured at the single molecule level-to the transcriptional status of genes. By stitching partially overlapping long reads and clustering them by shared GpC-accessibility patterns, we stratify CTCF into graded binding states on individual molecules, classify RNA polymerase states at promoters/gene bodies, and infer when spatially separated loci are coordinately activated and occupy loop-competent configurations on the same molecules. When applied to Sox2, Hoxa, and Klf1 regions, cluster-based nano-NOMe-seq phasing reveals how specific topologies bias polymerase behavior and multi-locus activity in ways that bulk assays or locus-engineered imaging cannot fully capture.

Journal Article↗

PubMed2025

Multiple clades of regulators contribute to bacterial phosphate homeostasis and pathogenesis.

Phosphate is both essential for life and toxic, necessitating the tight regulation of its acquisition. Based on Escherichia coli, most bacteria are thought to use a single accessory protein that monitors import to regulate phosphate homeostasis. This work reveals that most bacteria possess multiple distinct families of accessory regulators with each family regulating homeostasis in conjunction with a unique importer family. The antibiotic-resistant pathogen Staphylococcus aureus can obtain phosphate from divergent environments and possesses accessory-transporter pairs from all three identified groups. Investigations with S. aureus revealed that all three accessory proteins can regulate phosphate homeostasis, but that there is a hierarchy, which is dictated by the environment. Multiple accessory regulators are independently necessary for S. aureus to cause infection. Thus, microbes possess not one, but multiple distinct groups of accessory regulatory proteins and this diversity enables them to control phosphate homeostasis across environments, including those encountered during infection.

PhoPR↗

PubMed2025

Genomic and phenotypic comparison of Saccharomyces cerevisiae and Saccharomyces boulardii.

Saccharomyces boulardii is a widely used probiotic yeast with clinical efficacy against certain gastrointestinal disorders. Although genomically related to S. cerevisiae, the extent to which S. boulardii harbors distinct probiotic-relevant traits remains incompletely defined, particularly across commercially distributed strains. Here, we performed comparative genomic, physiological, and functional analyses of five S. boulardii strains and three S. cerevisiae strains, including baker's and laboratory variants. S. boulardii strains shared conserved genetic features and exhibited a conserved chromosomal inversion on chromosome XVI, lower copy numbers of CAZyme genes, and lineage-specific amino acid substitutions in central and tryptophan catabolism pathways-potentially underlying elevated production of immunomodulatory metabolites. S. boulardii strains also exhibited enhanced acid tolerance, elevated acetate and succinate production, and robust immunomodulatory activity, including suppression of IL-8 secretion and NF-κB, and consistent activation of the aryl hydrocarbon receptor (AhR) compared to S. cerevisiae. In contrast, S. cerevisiae strains displayed greater bile salt tolerance and faster growth under aerobic and anaerobic conditions at both 30°C and 37°C but lacked consistent anti-inflammatory effects or AhR agonism. Metabolic and immunological phenotypes varied with oxygen availability and strain background. Despite high genomic similarity, S. cerevisiae and S. boulardii exhibit distinct functional capacities relevant to probiotic efficacy. These findings help define speciesand strain-specific features that inform the development and regulatory evaluation of next-generation yeast probiotics.

AhR activation↗

PubMed2025

Spatial Metabolomics Reveals the Role of Penicillic Acid in Cheese Rind Microbiome Disruption by a Spoilage Fungus.

Microbial interactions in cheese rinds influence community structure, food safety, and product quality. But the chemical mechanisms that mediate microbial interactions in cheeses and other fermented foods are generally not known. Here, we investigate how the spoilage mold Aspergillus westerdijkiae chemically inhibits beneficial cheese-rind bacteria using a combination of omics technologies. In cheese rind community and co-culture experiments, A. westerdijkiae strongly inhibited most cheese rind community members. In co-culture with Staphylococcus equorum, A. westerdijkiae strongly affected bacterial gene expression, including upregulation of a putative bceAB gene cluster that is associated with resistance to antimicrobial compounds in other bacteria. Mass spectrometry imaging (MSI) revealed spatially localized production of secondary metabolites, including penicillic acid and ochratoxin B at the fungal-bacterial interface. Integration of LC-MS/MS and genome annotations confirmed the presence of additional bioactive metabolites, such as notoamides and circumdatins. Fungal metabolic responses varied by bacterial partner, suggesting species-specific chemical strategies. Notably, penicillic acid levels increased 2.5-fold during interaction with Brachybacterium, and experiments with purified penicillic acid showed inhibition of a range of cheese rind bacteria. These findings show that A. westerdijkiae deploys a context-dependent arsenal of mycotoxins and other metabolites, disrupting microbial community assembly in cheese rinds.

Aspergillus westerdijkiae↗

PubMed2025

SFPQ Promotes Homologous Recombination via mRNA Stabilization of RAD51 and Its Paralogs.

Double-strand break (DSB) repair occurs through non-homologous end joining (NHEJ) or homologous recombination (HR). To identify non-canonical factors that influence DSB repair outcomes, we parsed data from pooled genetic screens. Through this approach, we identified the splicing factor SFPQ, which has been previously reported to associate with DSBs and promote repair. Here, we show that SFPQ depletion alters DSB repair via HR. However, in contrast to other published work, we find that SFPQ does not localize to DSBs but instead stabilizes the expression of RAD51 and its paralogs independently of p53 activation or DNA damage. Our findings suggest that SFPQ contributes to constitutive DSB repair by maintaining RAD51 paralog mRNA stability rather than through direct interaction with DSBs or RAD51 protein and highlight indirect mechanisms by which RNA-binding proteins can influence genome stability.

DNA double-strand break repair (DSB repair)↗

PubMed2025

Human-specific features of the cerebellum and ZP2-regulated synapse development.

Understanding the unique features of the human brain compared to non-human primates has long intrigued humankind. The cerebellum refines motor coordination and cognitive functions, contributing to the evolutionary development of human adaptability and dexterity. To identify shared and divergent features across primates, we conducted single-nucleus transcriptomic and chromatin accessibility profiling of the adult cerebellar cortex in humans, chimpanzees, macaques, and marmosets. We revealed human-specific transcriptomic and regulatory features, particularly those involved in synaptogenesis. Notably, we identified an enrichment of the sperm receptor zona pellucida glycoprotein 2 (ZP2) and its potential interactors, known for their roles in gamete interaction, in human granule cells. Experimental data show that ZP2 expression in human granule cells is induced by pontine mossy fibers, reducing synaptic proteins at pontocerebellar glomerular synapses, and decreasing cerebellar neuron electrophysiological activity. This unexpected co-option of ZP2 in human-specific synapse regulation provides insights into the evolutionary specialization of the human cerebellum.

Brain evolution↗

PubMed2025

Nanoscopy Reveals Heparan Sulfate Clusters as Docking Sites for SARS-CoV-2 Attachment and Entry.

Virus entry is thought to involve binding a unique receptor for cell attachment and cytosolic entry. For SARS-CoV-2 underlying the COVID-19 pandemic, angiotensin-converting enzyme 2 (ACE2) is widely assumed as the receptor. Using advanced light microscopy to resolve individual virions and receptors, we found instead that heparan sulfate (HS), not ACE2, mediates SARS-CoV-2 cell-surface attachment and subsequent endocytosis. ACE2 functions only downstream of HS to enable viral genome expression. Instead of binding single HS molecules that electrostatically interact with viral surface proteins weakly, SARS-CoV-2 binds clusters of ~6-137 HS molecules projecting 60-410 nm above the plasma membrane. These tall, HS-rich clusters, present at about one per 6 μm2, act as docking sites for viral attachment. Blocking HS binding with the clinically used HS-binding agent pixantrone strongly inhibited the clinically relevant SARS-CoV-2 Omicron JN.1 subvariant from attaching to and infecting human airway cells. This work establishes a revised entry paradigm in which HS clusters mediate SARS-CoV-2 attachment and endocytosis, with ACE2 acting downstream, thereby identifying HS interactions as a key anti-COVID-19 strategy. This paradigm and its therapeutic implications may apply broadly beyond COVID-19 because, analogous to SARS-CoV-2, HS binds many other viruses but is only considered an attachment regulator.

Journal Article↗

PubMed2025

Panorama of Chromosomal Instability in Lung Cancer.

Lung cancer is a highly heterogeneous disease primarily driven by tobacco smoking. About 20% of lung cancers occur among patients who have never smoked (LCINS) with differences in patient ancestry, sex, tumor histology, and clinical features. Our understanding of chromosomal instability in lung cancer, especially LCINS, is still limited. Here, we perform a comprehensive study of 182,429 somatic structural variations (SVs) detected in 1,209 whole-genome sequenced lung cancers, of which 864 LCINS. SVs are more abundant in tumors from patients who have smoked (LCSS); however, they are more complex and play more important roles in tumorigenesis in LCINS. EGFR mutations and KRAS mutations profoundly and independently shape the SV landscape. EGFR-mutant tumors have higher SV burden and more cancer-driving SVs. In contrast, KRAS mutations are associated with lower SV burden and less driver SVs. We decompose 16 SV signatures for both complex and simple SVs that likely represent divergent molecular mechanisms. The SV breakpoints have distinct distributions across the genome depending on the signatures due to mutagenic mechanisms and positive selection. Many established cancer-driving genes are recurrently rearranged by multiple SV signatures suggesting functional convergence of these genome instability mechanisms.

Journal Article↗

PubMed2025

Endogenous retroelements promote tolerance to dietary antigens.

Retroelements are transposable elements that represent a significant portion of eukaryotic genomes. Here, we show that constitutive expression of endogenous retroelements play a key regulatory role in the acquisition of food tolerance. Specifically, inhibition of retroelement reverse transcription abolishes tolerance to dietary antigens and promotes allergic responses. This phenomenon is associated with impaired regulatory T cell differentiation/accumulation and altered dendritic cell tolerogenic function. Mechanistically, innate sensing of retroelement-derived cDNA via cGAS/STING within gut epithelial cells promotes a local tolerogenic milieu. Thus, within the gut, immune reactivity to retroelements act as a local tonic signal required for regulatory T cell induction and differentiation, thereby preventing allergic responses to food. Collectively, these findings uncover retroelements as key regulatory elements and essential allies in maintaining immune tolerance.

Journal Article↗

PubMed2025

Structural Basis of Cold and Menthol Sensing by TRPM8.

The transient receptor potential melastatin member 8 (TRPM8) is a polymodal ion channel that senses cold and menthol in mammals. Despite prior structural studies, the mechanisms by which cold and menthol activate TRPM8 remain unresolved. Here, we present cryo-EM structures representing the cold and menthol-dependent activation trajectories, combined with extensive functional analyses. We captured snapshots of cooling-dependent pore opening, which involves dramatic pore rearrangement, suggesting a mechanism for cold sensing. Moreover, menthol binds dynamically to induce channel activation, which may underlie menthol specificity for TRPM8. Finally, we show how TRPM8 integrates multiple modalities (cold and menthol) through overlapping but non-identical pathways, revealing the temperature-specific "cold spot". These findings enhance our understanding of the molecular basis of physically and chemically induced cool sensation in mammals.

Journal Article↗

PubMed2025

Engineered histones reshape chromatin in human cells.

Histone proteins and their variants have been found to play crucial and specialized roles in chromatin organization and the regulation of downstream gene expression; however, the relationship between histone sequence and its effect on chromatin organization remains poorly understood, limiting our functional understanding of sequence variation between distinct subtypes and across evolution and frustrating efforts to rationally design synthetic histones that can be used to engineer specified cell states. Here, we make the first advance towards engineered histone-driven chromatin organization. By expressing libraries of sequence variants of core histones in human cells, we identify variants that dominantly modulate chromatin structure. We further interrogate variants using a combination of imaging, proteomics, and genomics to reveal both cis and trans-acting mechanisms of effect. Functional screening with transcription factor libraries identifies transcriptional programs that are facilitated by engineered histone expression. Double mutation screens combined with protein language models allow us to learn sequence-to-function patterns and design synthetic histone proteins optimized to drive specific chromatin states. This work establishes a foundation for the high-throughput evaluation and engineering of chromatin-associated proteins and positions histones as tunable nodes for understanding and modulating mesoscale chromatin organization.

Journal Article↗