eLife: latest articles by subject

Revealing global stoichiometry conservation architecture in cells from Raman spectral patterns

kenichiro_kamei@cell.c.u-tokyo.ac.jp (Hidenori Nakaoka) — Tue, 14 Apr 2026 00:00:00 +0000

Cells can adapt to various environments by changing their biomolecular profiles while maintaining physiological homeostasis. What organizational principles in cells enable the simultaneous realization of adaptability and homeostasis? To address this question, we measure Raman scattering light from Escherichia coli cells under diverse conditions, whose spectral patterns convey their comprehensive molecular composition. We reveal that dimension-reduced Raman spectra can predict condition-dependent proteome profiles. Quantitative analysis of the Raman-proteome correspondence characterizes a low-dimensional hierarchical stoichiometry-conserving proteome structure. The network centrality of each gene in the stoichiometry conservation relations correlates with its essentiality and evolutionary conservation, and these correlations are preserved from bacteria to human cells. Furthermore, stoichiometry-conserving core components obey growth law and ensure homeostasis across conditions, whereas peripheral stoichiometry-conserving components enable adaptation to specific conditions. Mathematical analysis reveals that the stoichiometrically constrained architecture is reflected in major changes in Raman spectral patterns. These results uncover coordination of global stoichiometric balance in cells and demonstrate that vibrational spectroscopy can decipher such biological constraints beyond statistical or machine-learning inference of cellular states.

Competition for the conserved branch point sequence influences physiological outcomes in pre-mRNA splicing

wsfagg@UTMB.EDU (Haiping Hao) — Fri, 20 Mar 2026 00:00:00 +0000

Recognition of the intron branch point during spliceosome assembly is a multistep process that can influence mRNA structure and levels. A branch point sequence motif UACUAAC is variably conserved in eukaryotic genomes, but in some organisms, more than one protein can recognize it. Here, we show that SF1 and Quaking (QKI) compete for a subset of intron branch sites with the sequence ACUAA in mammalian cells. SF1 activates exon inclusion through this sequence, but QKI represses the inclusion of alternatively spliced exons with this intron branch point sequence. Using mutant reporters derived from a natural intron with two branch site-like sequences, we find that when either branch point sequence is mutated, the other is utilized; however, when both are present, neither is used due to high-affinity binding and strong splicing repression by QKI. QKI occupancy at the dual branch site directly prevents SF1 binding and the subsequent recruitment of spliceosome-associated factors. Finally, ectopic expression of QKI in budding yeast (which lacks QKI) is lethal, at least in part due to widespread splicing repression. In conclusion, QKI can function as a splicing repressor by directly competing with SF1/BBP for a subset of branch point sequences that closely mirror its high-affinity binding site.

The impact of stability considerations on genetic fine-mapping

nilah@berkeley.edu (Alan J Aw) — Mon, 16 Mar 2026 00:00:00 +0000

Fine-mapping methods, which aim to identify genetic variants responsible for complex traits following genetic association studies, typically assume that sufficient adjustments for confounding within the association study cohort have been made, for example, through regressing out the top principal components (i.e., residualization). Despite its widespread use, however, residualization may not completely remove all sources of confounding. Here, we propose a complementary stability-guided approach that does not rely on residualization, which identifies consistently fine-mapped variants across different genetic backgrounds or environments. Simulations show that stability guidance neither outperforms nor underperforms residualization, but each approach picks up different variants considerably often. Critically, prioritizing variants that match between the residualization and stability-guided approaches enhances recovery of causal variants. We further demonstrate the utility of the stability approach by applying it to fine-map eQTLs in the GEUVADIS data. Using 378 different functional annotations of the human genome, including recent deep learning-based annotations (e.g., Enformer), we compare enrichments of these annotations among variants for which the stability and traditional residualization-based fine-mapping approaches agree against those for which they disagree and find that the stability approach enhances the power of traditional fine-mapping methods in identifying variants with functional impact. Finally, in cases where the two approaches report distinct variants, our approach identifies variants comparably enriched for functional annotations. Our findings suggest that the stability principle, as a conceptually simple device, complements existing approaches to fine-mapping, reinforcing recent advocacy of evaluating cross-population and cross-environment portability of biological findings. To support visualization and interpretation of our results, we provide a Shiny app, accessible at https://github.com/songlab-cal/StableFM.

Human-specific lncRNAs contributed critically to human evolution by distinctly regulating gene expression

zhuhao@smu.edu.cn (Hao Zhu) — Fri, 13 Mar 2026 00:00:00 +0000

What genes and regulatory sequences critically differentiate modern humans from apes and archaic humans, which share highly similar genomes but show distinct phenotypes, has puzzled researchers for decades. Previous studies examined species-specific protein-coding genes and related regulatory sequences, revealing that birth, loss, and changes in these genes and sequences drive speciation and evolution. However, investigations of species-specific lncRNA genes and related regulatory sequences, which regulate substantial genes, remain limited. We identified human-specific (HS) lncRNAs from GENCODE-annotated human lncRNAs, predicted their DNA-binding domains (DBDs) and DNA-binding sites (DBSs), analyzed DBS sequences in modern humans (CEU, CHB, and YRI), archaic humans (Altai Neanderthals, Denisovans, and Vindija Neanderthals), and chimpanzees, and investigated how HS lncRNAs and their DBSs have influenced gene expression in archaic and modern humans. Our results suggest that these lncRNAs and DBSs have substantially reshaped gene expression, and this reshaping has evolved continuously from archaic to modern humans, enabling humans to adapt to new environments and lifestyles, promoting brain evolution, and resulting in cross-population differences. The parallel analysis of gene expression in GTEx tissues by HS transcription factors (TFs) and their DBSs indicates that HS lncRNAs have reshaped gene expression in the brain more significantly than HS TFs.

A genome-wide MAGIC kit for recombinase-independent mosaic analysis in Drosophila

chun.han@cornell.edu (Ann T Yeung) — Wed, 11 Mar 2026 00:00:00 +0000

Mosaic analysis has been instrumental in advancing developmental and cell biology. Most current mosaic techniques rely on exogenous site-specific recombination sequences that need to be introduced into the genome, limiting their application. Mosaic analysis by gRNA-induced crossing-over (MAGIC) was recently developed in Drosophila to eliminate this requirement by inducing somatic recombination through CRISPR/Cas9-generated DNA double-strand breaks. However, MAGIC has not been widely adopted because gRNA markers, a required component for this technique, are not yet available for most chromosomes. Here, we present a complete, genome-wide gRNA-marker kit that incorporates optimized designs for enhanced clone induction and more effective clone labeling in both positive MAGIC (pMAGIC) and negative MAGIC (nMAGIC). With this kit, we demonstrate clonal analysis in a broad range of Drosophila tissues, including cell types that have been difficult to analyze using recombinase-based systems. Notably, MAGIC enables clonal analysis of pericentromeric genes, deficiency chromosomes and in interspecific hybrid animals, opening new avenues for gene function study, rapid gene discovery, and understanding cellular basis of speciation. This MAGIC kit complements existing systems and makes mosaic analysis accessible to address a wider range of biological questions.

Cell type-specific network analysis in Diversity Outbred mice identifies genes potentially responsible for human bone mineral density GWAS associations

crf2s@virginia.edu (Charles Farber) — Wed, 11 Mar 2026 00:00:00 +0000

Genome-wide association studies (GWASs) have identified many sources of genetic variation associated with bone mineral density (BMD), a clinical predictor of fracture risk and osteoporosis. Aside from the identification of causal genes, other difficult challenges to informing GWAS include characterizing the roles of predicted causal genes in disease and providing additional functional context, such as the cell-type predictions or biological pathways in which causal genes operate. Leveraging single-cell transcriptomics (scRNA-seq) can assist in informing BMD GWAS by linking disease-associated variants to genes and providing a cell-type context for which these causal genes drive disease. Here, we use large-scale scRNA-seq data from bone marrow-derived stromal cells cultured under osteogenic conditions (BMSC-OBs) from Diversity Outbred (DO) mice to generate cell type-specific networks and contextualize BMD GWAS-implicated genes. Using trajectories inferred from the scRNA-seq data that map cell state transitions, we identify networks enriched with genes that exhibit the most dynamic changes in expression across trajectories. We discover 21 network driver genes, which are likely to be causal for human BMD GWAS associations that colocalize with expression/splicing quantitative trait loci (eQTLs/sQTLs). These driver genes, including Fgfrl1 and Tpx2, along with their associated networks, are predicted to be novel regulators of BMD via their roles in the differentiation of mesenchymal lineage cells. In this work, we showcase the use of single-cell transcriptomics from mouse bone-relevant cells to inform human BMD GWAS and prioritize genetic targets with potential causal roles in the development of osteoporosis.

Defining the chromatin-associated protein landscapes on Trypanosoma brucei repetitive elements using synthetic TALE proteins

keith.matthews@ed.ac.uk (Christos Spanos) — Tue, 10 Mar 2026 00:00:00 +0000

Kinetoplastids, such as Trypanosoma brucei, are eukaryotes that likely separated from the main lineage at an exceptionally early point in evolution. Consequently, many aspects of kinetoplastid biology differ significantly from other eukaryotic model systems, including yeasts, plants, worms, flies, and mammals. As in many eukaryotes, the T. brucei genome contains repetitive elements at various chromosomal locations, including centromere- and telomere-associated repeats and interspersed retrotransposon elements. T. brucei also contains intermediate-sized and mini-chromosomes that harbour abundant 177 bp repeat arrays and 70 bp repeat elements implicated in Variable Surface Glycoprotein (VSG) gene switching. In many eukaryotes, repetitive elements are assembled in specialised chromatin such as heterochromatin; however, apart from centromere- and telomere-associated repeats, little is known about chromatin-associated proteins that decorate these and other repetitive elements in kinetoplastids. Here, we utilise affinity selection of synthetic TALE DNA binding proteins designed to target specific repeat elements to identify enriched proteins by proteomics. Validating the approach, a telomere repeat binding TelR-TALE identifies many proteins previously implicated in telomere function. Furthermore, the 70R-TALE designed to bind 70 bp repeats indicates that proteins involved in DNA repair are enriched on these elements that reside adjacent to VSG genes. Interestingly, the 177 bp repeat binding 177R-TALE enriches for many kinetochore proteins, suggesting that intermediate-sized and mini-chromosomes assemble kinetochores related in composition to those located on the main megabase chromosomes. This provides a first insight into the chromatin landscape of repetitive regions of the trypanosome genome with relevance for their mechanisms of chromosome integrity, immune evasion, and cell replication.

Nup107 is a crucial regulator of torso-mediated metamorphic transition in Drosophila melanogaster

jyotsna19@iiserb.ac.in (Jyotsna Kawadkar) — Tue, 10 Mar 2026 00:00:00 +0000

Nuclear pore complexes (NPCs), composed of nucleoporins (Nups), affect nucleocytoplasmic transport, thus influencing cell division and gene regulation. Nup107 subcomplex members have been studied in housekeeping functions, diseases, and developmental disorders. We report a unique regulatory function for Nup107 in metamorphic transition during Drosophila development. RNA interference (RNAi)-mediated Nup107-depleted larvae were arrested in the third-instar larval stage with no signs of pupariation. This lack of pupariation is primarily due to inhibited nuclear translocation and transcriptional activation by EcR. We demonstrate the involvement of Nup107 in the transcription of the Halloween genes, modulating ecdysone biosynthesis and the EcR pathway activation. The regulation of EcR-mediated metamorphosis by the receptor tyrosine kinase, torso, is well documented. Accordingly, overexpression of the torso and MAP-kinase pathway activator, ras^V12, in the Nup107 depletion background rescues the phenotypes, implying that Nup107 is an epistatic regulator of Torso-mediated activation of EcR signaling during metamorphosis.

EPB41L4A-AS1 long noncoding RNA acts in both cis- and trans-acting transcriptional regulation and controls nucleolar biology

igor.ulitsky@weizmann.ac.il (Alan Monziani) — Tue, 10 Mar 2026 00:00:00 +0000

Mammalian genomes are pervasively transcribed into long noncoding RNAs (lncRNAs), whose functions and modes of action remain poorly understood. EPB41L4A-AS1 is an evolutionarily conserved, broadly and highly expressed lncRNA that produces the H/ACA snoRNA SNORA13 from one of its introns. We studied the consequences of EPB41L4A-AS1 perturbation in breast cancer cells and found that it acts both in cis, to enhance transcription of the proximal EPB41L4A gene and additional genes in its two flanking topologically associated domains, and in trans by broadly regulating gene expression, including expression of snoRNAs, transcription of genes involved in nucleolar biology and the distribution of nucleolar proteins. These effects are phenocopied by the loss of SUB1, an interactor of EPB41L4A-AS1, and are observed following transient perturbations of EPB41L4A-AS1 that do not affect steady-state SNORA13 levels or the rRNA modification it helps install. Exogenous expression of the full-length EPB41L4A-AS1 locus but not SNORA13 expression can rescue the trans-acting transcriptional effects of its perturbation. The EPB41L4A-AS1 gene is thus a versatile locus producing RNA molecules acting on multiple levels for key cellular functions.

JAX Animal Behavior System (JABS), a genetics-informed, end-to-end advanced behavioral phenotyping platform for the laboratory mouse

Vivek.Kumar@jax.org (Anshul Choudhary) — Mon, 02 Mar 2026 00:00:00 +0000

Automated detection of complex animal behavior remains a challenge in neuroscience. Developments in computer vision have greatly advanced automated behavior detection and allow high-throughput preclinical and mechanistic studies. An integrated hardware and software solution is necessary to facilitate the adoption of these advances in the field of behavioral neurogenetics, particularly for non-computational laboratories. We have published a series of papers using an open field arena to annotate complex behaviors such as grooming, posture, and gait as well as higher-level constructs such as biological age and pain. Here, we present our integrated rodent phenotyping platform, JAX Animal Behavior System (JABS), to the community for data acquisition, machine learning-based behavior annotation and classification, classifier sharing, and genetic analysis. The JABS Data Acquisition Module (JABS-DA) enables uniform data collection with its combination of 3D hardware designs and software for real-time monitoring and video data collection. JABS-Active Learning Module (JABS-AL) allows behavior annotation, classifier training, and validation. We introduce a novel graph-based framework (ethograph) that enables efficient boutwise comparison of JABS-AL classifiers. JABS-Analysis and Integration Module (JABS-AI), a web application, facilitates users to deploy and share any classifier that has been trained on JABS, reducing the effort required for behavior annotation. It supports the inference and sharing of the trained JABS classifiers and downstream genetic analyses (heritability and genetic correlation) on three curated datasets spanning 168 mouse strains that we are publicly releasing alongside this study. This enables the use of genetics as a guide to proper behavior classifier selection. This open-source tool is an ecosystem that allows the neuroscience and genetics community to share advanced behavior analysis and reduces the barrier to entry into this new field.

Non-visual light modulates behavioral memory and gene expression in Caenorhabditis elegans

Dengke.Ma@ucsf.edu (Bingying Wang) — Tue, 24 Feb 2026 00:00:00 +0000

Visible light influences a range of physiological processes, yet how animals respond to it independently of the visual system remains largely unknown. Here, we uncover a previously undescribed light-induced transcriptional pathway that modulates behavioral plasticity in Caenorhabditis elegans, a roundworm without eyes. We demonstrate that ambient visible light or controlled-intensity visible-spectrum LED activates an effector gene cyp-14A5 in non-neuronal tissues through the bZIP transcription factors ZIP-2 and CEBP-2. Light induction of cyp-14A5 is more prominent at shorter wavelengths but is independent of the known blue light receptors LITE-1 and GUR-3 in C. elegans. This bZIP-dependent genetic pathway in non-neuronal tissues enhances behavioral adaptability and olfactory memory, suggesting a body-brain communication axis. Furthermore, we use the light-responsive cyp-14A5 promoter to drive ectopic gene expression, causing synthetic light-induced sleep and rapid aging phenotypes in C. elegans. These findings advance our understanding of light-responsive mechanisms outside the visual system and offer a new genetic tool for visible light-inducible gene expression in non-neuronal tissues.

Scaling up efforts to target evolving viruses

hs743@cam.ac.uk (Henrik Salje) — Mon, 23 Feb 2026 00:00:00 +0000

High-throughput neutralisation tests could lead to a better understanding of the evolution of human influenza.

Impaired excitability of fast-spiking neurons in a novel mouse model of KCNC1 epileptic encephalopathy

goldberge@chop.edu (Ala Somarowthu) — Wed, 18 Feb 2026 00:00:00 +0000

The recurrent pathogenic variant KCNC1-p.Ala421Val (A421V) is a cause of developmental and epileptic encephalopathy characterized by moderate-to-severe developmental delay/intellectual disability, and infantile-onset treatment-resistant epilepsy with multiple seizure types, including myoclonic seizures. Yet, the mechanistic basis of this disease, and of the KCNC1 disease spectrum, remains unclear. KCNC1 encodes Kv3.1, a voltage-gated potassium channel subunit that is strongly and selectively expressed in neurons capable of generating action potentials at high frequency, including parvalbumin-positive fast-spiking GABAergic inhibitory interneurons in cerebral cortex (PV-INs) that are known to be important for cognitive function and plasticity as well as control of network excitation to prevent seizures. In this study, we generate a novel transgenic mouse model with conditional expression of the A421V pathogenic missense variant (Kcnc1-A421V/+ mice) to explore the specific physiological mechanisms of KCNC1 developmental and epileptic encephalopathy. Our results indicate that global heterozygous expression of the A421V variant leads to cognitive impairment, epilepsy, and premature lethality. We observe decreased PV-IN cell surface expression of Kv3.1 via immunohistochemistry, decreased voltage-gated potassium current density in PV-INs using outside-out nucleated macropatch recordings in brain slice, and profound impairments in the intrinsic excitability of cerebral cortex PV-INs (but not excitatory neurons) via current-clamp electrophysiology. In vivo two-photon calcium imaging revealed altered activity in Kcnc1-A421V/+ PV-INs and excitatory cells, as well as hypersynchronous discharges correlated with brief paroxysmal movements that were subsequently shown to be myoclonic seizures on electroencephalography. We found alterations in PV-IN-mediated inhibitory neurotransmission in young adult but not juvenile Kcnc1-A421V/+ mice relative to wild-type controls. Together, these results establish the specific impact of the recurrent Kv3.1-A421V variant on neuronal excitability and synaptic physiology across development to drive network dysfunction underlying KCNC1 epileptic encephalopathy.

SETDB1 enables development beyond cleavage stages by extinguishing the MERVL-driven two-cell totipotency transcriptional program in the mouse embryo

piroska.szabo@vai.org (Ji Liao) — Mon, 16 Feb 2026 00:00:00 +0000

Loss of maternal SETDB1, a histone H3K9 methyltransferase, leads to developmental arrest prior to implantation, with very few mouse embryos advancing beyond the eight-cell stage, which is currently unexplained. We genetically investigate SETDB1’s role in the epigenetic control of the transition from totipotency to pluripotency—a process demanding precise timing and forward directionality. Through single-embryo total RNA sequencing of two-cell and eight-cell embryos, we find that Setdb1^mat-/+ embryos fail to extinguish one-cell and two-cell transient genes—alongside persistent expression of MERVL retroelements and MERVL-driven chimeric transcripts that define the totipotent state in mouse two-cell embryos. Comparative bioinformatics reveals that SETDB1 acts at MT2 LTRs and MERVL-driven chimeric transcripts, which normally acquire H3K9me3 during early development. The dysregulated targets substantially overlap with DUXBL-responsive genes, indicating a shared regulatory pathway for silencing the two-cell transcriptional program. We establish maternal SETDB1 as a critical chromatin regulator required to extinguish retroelement-driven totipotency networks and ensure successful preimplantation development.

Ribosomal RNA synthesis by RNA polymerase I is subject to premature termination of transcription

olivier.gadal@univ-tlse3.fr (Annick Lesne) — Thu, 12 Feb 2026 00:00:00 +0000

The RNA polymerase I (Pol I) enzyme that synthesizes large rRNA precursors exhibits a high rate of pauses during elongation, indicative of a discontinuous process. We show here that premature termination of transcription (PTT) by Pol I in yeast Saccharomyces cerevisiae is a critical regulatory step limiting rRNA production in vivo. The Pol I mutant, SuperPol (RPA135-F301S), produces 1.5-fold more rRNA than the wild type (WT). Combined CRAC and rRNA analysis link increased rRNA production in SuperPol to reduced PTT, resulting in shifting polymerase distribution toward the 3’ end of rDNA genes. In vitro, SuperPol shows reduced nascent transcript cleavage, associated with more efficient transcript elongation after pauses, to the detriment of transcriptional fidelity. Notably, SuperPol is resistant to BMH-21, a drug impairing Pol I elongation and inducing proteasome-mediated degradation of Pol I subunits. Compared to WT, SuperPol maintains subunit stability and sustains high transcription levels upon BMH-21 treatment. These comparative results show that PTT is alleviated in SuperPol while it is stimulated by BMH-21 in WT Pol I.

Heterogeneous associations of polygenic indices of 35 traits with mortality: a register-linked population-based follow-up study

hannu.lahtinen@helsinki.fi (Andrea Ganna) — Wed, 11 Feb 2026 00:00:00 +0000

Four women whose pioneering contributions to science have been largely overlooked

lcmthomann@gmail.com (Julie Batut) — Wed, 11 Feb 2026 00:00:00 +0000

Ethel Browne Harvey and Hilde Pröscholdt Mangold did pioneering research in embryology, Ida Henrietta Hyde helped develop the first microelectrodes for the stimulation of single cells, and Marthe Gautier had a vital role in discovering that Down syndrome is caused by an extra copy of chromosome 21. So why are their names so little known by the scientific community at large?

Single-cell transcriptomics of X-ray irradiated Drosophila wing discs reveals heterogeneity related to cell-cycle status and cell location

ikh@berkeley.edu (Alexandra Verbeke) — Wed, 04 Feb 2026 00:00:00 +0000

Even seemingly homogeneous populations of cells can express phenotypic diversity in response to environmental changes. Thus, X-ray irradiation of tissues composed of diverse cell types can have complex outcomes. We have used single-cell RNA sequencing to study the effects of X-ray radiation on the Drosophila wing imaginal disc, a relatively simple tissue composed mostly of epithelial cells. Transcriptomic clustering of cells collected from the wing disc generates clusters that are mainly grouped based on proximodistal cell location. To quantify heterogeneity of gene expression among clusters, we adapted a metric used to study market concentration, the Herfindahl-Hirschman Index. Genes involved in DNA damage repair, defense against reactive oxygen species, cell cycle progression, and apoptosis are expressed relatively uniformly. In contrast, genes encoding a subset of ligands, notably cytokines that activate the JAK/STAT pathway, some transcription factors, including Ets21C, previously implicated in regeneration, and several signaling proteins are expressed more regionally. Though the radiation-responsive transcription factor p53 is expressed relatively uniformly in the wing disc, several regionally induced genes still require p53 function, indicating that regional and radiation-induced factors combine to regulate their expression. We also examined heterogeneity within regions using a clustering approach based on cell cycle gene expression. A subpopulation of cells, characterized by high levels of tribbles expression, is amplified in irradiated discs. Remarkably, this subpopulation accounts for a considerable fraction of radiation-induced gene expression, indicating that cellular responses are non-uniform even within regions. Thus, both inter-regional and intra-regional heterogeneity are important features of tissue responses to X-ray radiation.

Polymorphisms in intron 1 of HLA-DRA differentially associate with type 1 diabetes and celiac disease and implicate involvement of complement system genes C4A and C4B

ozkanaydemir@gmail.com (Agnes Andersson Svärd) — Mon, 02 Feb 2026 00:00:00 +0000

Polymorphisms in genes in the human leukocyte antigen (HLA) class II region comprise the most important inherited risk factors for many autoimmune diseases, including type 1 diabetes (T1D) and celiac disease (CD): both diseases are positively associated with the HLA-DR3 haplotype (DRB1*03:01-DQA1*05:01-DQB1*02:01). Studies of two different populations have recently documented that T1D susceptibility in HLA-DR3 homozygous individuals is stratified by a haplotype consisting of three single nucleotide polymorphisms (‘tri-SNP’) in intron 1 of the HLA-DRA gene. In this study, we use a large cohort from the longitudinal ‘The Environmental Determinants of Diabetes in the Young’ (TEDDY) study to further refine the tri-SNP association with T1D and with autoantibody-defined T1D endotypes. We found that the tri-SNP association is primarily in subjects whose first-appearing T1D autoantibody is to insulin. In addition, we discovered that the tri-SNP is also associated with CD, and that the particular tri-SNP haplotype (‘101’) that is negatively associated with T1D risk is positively associated with risk for CD. The opposite effect of the tri-SNP haplotype on two DR3-associated diseases can enhance and refine current models of disease prediction based on genetic risk. Finally, we investigated possible functional differences between the individuals carrying high and low-risk tri-SNP haplotypes and found that differences in complement system genes C4A and C4B may underlie the observed divergence in disease risk.

Single-cell profiling of trabecular meshwork identifies mitochondrial dysfunction in a glaucoma model that is protected by vitamin B3 treatment

william.stamer@duke.edu (Bryan Jones) — Tue, 20 Jan 2026 00:00:00 +0000

Since the trabecular meshwork (TM) is central to intraocular pressure (IOP) regulation and glaucoma, a deeper understanding of its genomic landscape is needed. We present a multimodal, single-cell resolution analysis of mouse limbal cells (includes TM). In total, we sequenced 9,394 wild-type TM cell transcriptomes. We discovered three TM cell subtypes with characteristic signature genes validated by immunofluorescence on tissue sections and whole-mounts. The subtypes are robust, being detected in datasets for two diverse mouse strains and in independent data from two institutions. Results show compartmentalized enrichment of critical pathways in specific TM cell subtypes. Distinctive signatures include increased expression of genes responsible for (1) extracellular matrix structure and metabolism (TM1 subtype), (2) secreted ligand signaling to support Schlemm’s canal cells (TM2), and (3) contractile and mitochondrial/metabolic activity (TM3). ATAC-sequencing data identified active transcription factors in TM cells, including LMX1B. Mutations in LMX1B cause high IOP and glaucoma. LMX1B is emerging as a key transcription factor for normal mitochondrial function, and its expression is much higher in TM3 cells than other limbal cells. To understand the role of LMX1B in TM function and glaucoma, we single-cell sequenced limbal cells from Lmx1b^V265D/+ mutant mice (2491 TM cells). In Lmx1b^V265D/+ mice, TM3 cells were uniquely affected by pronounced mitochondrial pathway changes. Mitochondria in TM cells of Lmx1b^V265D/+ mice are swollen with a reduced cristae area, further supporting a role for mitochondrial dysfunction in the initiation of IOP elevation in these mice. Importantly, treatment with vitamin B3 (nicotinamide), which enhances mitochondrial function and metabolic resilience in other contexts, significantly protected Lmx1b mutant mice from IOP elevation.

The RNA-binding protein HuR modulates the expression of the disease-linked CCL2 rs1024611G-rs13900T haplotype

Srinivas.Mummidi@tamusa.edu (Alvaro Diaz-Badillo) — Wed, 14 Jan 2026 00:00:00 +0000

CC-chemokine ligand 2 (CCL2) is involved in the pathogenesis of several diseases associated with monocyte/macrophage recruitment, such as HIV-associated neurocognitive disorder (HAND), tuberculosis, and atherosclerosis. The rs1024611 (alleles: A>G; G is the risk allele) polymorphism in the CCL2 cis-regulatory region is associated with increased CCL2 expression in vitro and ex vivo, leukocyte mobilization in vivo, and deleterious disease outcomes. However, the molecular basis for the rs1024611-associated differential CCL2 expression remains poorly characterized. It is conceivable that genetic variant(s) in linkage disequilibrium (LD) with rs1024611 could mediate such effects. Previously, we used rs13900 (alleles: C>T) in the CCL2 3′untranslated region (3′ UTR) that is in perfect LD with rs1024611 to demonstrate allelic expression imbalance (AEI) of CCL2 in heterozygous individuals. Here, we tested the hypothesis that the rs13900 could modulate CCL2 expression by altering mRNA turnover and/or translatability. The rs13900 T allele conferred greater stability to the CCL2 transcript when compared to the rs13900 C allele. The rs13900 T allele also had increased binding to Human Antigen R (HuR), an RNA-binding protein, in vitro and ex vivo. The rs13900 alleles imparted differential activity to reporter vectors and influenced the translatability of the reporter transcript. We further demonstrated the role of HuR in mediating allele-specific effects on CCL2 expression in overexpression and silencing studies. Our studies suggest that the differential interactions of HuR with rs13900 could modulate CCL2 expression and could in part explain the interindividual differences in CCL2-mediated disease susceptibility.

Finding a role for non-coding DNA in trypanosomes

Markus.Schmidt@lmu.de (Markus R Schmidt) — Tue, 13 Jan 2026 00:00:00 +0000

Non-coding DNA is essential for both humans and trypanosomes, despite the large evolutionary divergence between these two species.

Cross-species evaluation of TANGO2 homologs, including HRG-9 and HRG-10 in Caenorhabditis elegans, challenges a proposed role in heme trafficking

samuel_mackenzie@urmc.rochester.edu (Aaliya Naaz) — Thu, 08 Jan 2026 00:00:00 +0000

Mutations in the TANGO2 gene are associated with a severe neurometabolic disorder in humans, often presenting with life-threatening metabolic crisis. However, the function of TANGO2 protein remains unknown. It has recently been proposed that TANGO2 transports heme within and between cells, from areas with high heme concentrations to those with lower concentrations. Here, we demonstrate that prior heme-related observations in Caenorhabditis elegans lacking TANGO2 homologs HRG-9 and HRG-10 may be better explained by a previously unreported metabolic phenotype, characterized by reduced feeding, decreased lifespan and brood sizes, and poor motility. We also show that several genes not implicated in heme transport are upregulated in the low heme state and conversely demonstrate that hrg-9 in particular is highly responsive to oxidative stress, independent of heme status. Collectively, these data implicate bioenergetic failure and oxidative stress as potential factors in the pathophysiology of TANGO2 deficiency, in alignment with observations from human patients. Our group performed several experiments in yeast and zebrafish deficient in TANGO2 homologs and was unable to replicate prior findings from these models. Overall, we believe there is insufficient evidence to support heme transport as the primary function for TANGO2.

Replication stress-inducing ELF3 upregulation promotes BRCA1-deficient breast tumorigenesis in luminal progenitors

xiaozhou@pku.edu.cn (Jiadong Wang) — Wed, 07 Jan 2026 00:00:00 +0000

BRCA1 is a critical tumor suppressor, mutations in which greatly increase risks for many tumors in carriers, most notably breast cancer. Luminal progenitor cells (LPs) are the currently recognized cells of origin of BRCA1-deficient breast cancers. However, the reason why LPs are prone to transform with BRCA1 deficiency has not been elucidated. Here, using single-cell sequencing of human BRCA1 mutant breast cancers and RNA sequencing (RNA-seq) of BRCA1-deficient normal mammary cells, we reveal that replication stress is a feature of LPs and a driving factor during BRCA1-associated tumorigenesis. Mechanistically, replication stress and BRCA1 deficiency lead to significant upregulation of ELF3 expression. ELF3 can help suppress excessive genomic instability and promote LP transformation with BRCA1 deficiency. Moreover, ELF3 emerged as a core transcription factor regulating LP genes, leading to LP expansion. Our findings suggest that replication stress is a driving factor during BRCA1-associated tumorigenesis in luminal progenitor cells and elucidates the key role of ELF3 during this process.

Probing the proteome

whl243@as.edu.tw (Chia-Liang Cheng) — Wed, 07 Jan 2026 00:00:00 +0000

Raman spectroscopy can be used to predict cellular physiology and proteome composition in E. coli.

Identifying new targets in the fight against opioids

felaezza@utmb.edu (Fernanda Laezza) — Mon, 05 Jan 2026 00:00:00 +0000

Experiments reveal that a time-dependent epistatic interaction influences how mice respond to opioids, and that intracellular fibroblast growth factors also influence opioid sensitivity.

Deletion of the moeA gene in Flavobacterium IR1 drives structural color shift from green to blue and alters polysaccharide metabolism

aescdon94@gmail.com (Alexandre Campos) — Fri, 02 Jan 2026 00:00:00 +0000

Structural colors (SC), generated by light interacting with nano-structured materials, are responsible for the brightest and most vivid coloration in nature. Despite being widespread within the tree of life, there is little knowledge of the genes involved. Partial exceptions are some Flavobacteriia in which genes involved in a number of pathways, including gliding motility and polysaccharide metabolism, have been linked to SC. A previous genomic analysis of SC and non-SC bacteria suggested that the pterin pathway is involved in the organization of bacteria to form SC. Here, we focus on moeA, a molybdopterin molybdenum transferase. When this gene was deleted from Flavobacterium IR1, the knock-out mutant showed a strong blue shift in SC of the colony compared to the wild-type. The moeA mutant showed a particularly strong blue shift when grown on kappa-carrageenan and was upregulated for starch degradation. To further analyze the molecular changes, proteomic analysis was performed, showing the upregulation of various polysaccharide utilization loci, which supported the link between moeA and polysaccharide metabolism in SC. Overall, we demonstrated that a targeted approach, modifying a single gene identified by genomics, could change the optical properties of bacteria.

Neisseria gonorrhoeae LIN codes provide a robust, multi-resolution lineage nomenclature

odile.harrison@ndph.ox.ac.uk (Anastasia Unitt) — Wed, 31 Dec 2025 00:00:00 +0000

Investigation of the bacterial pathogen Neisseria gonorrhoeae is complicated by extensive horizontal gene transfer: a process which disrupts phylogenetic signals and impedes our understanding of population structure. The ability to consistently identify N. gonorrhoeae lineages is important for surveillance of this increasingly antimicrobial resistant organism, facilitating efficient communication regarding its epidemiology; however, conventional typing systems fail to reflect N. gonorrhoeae strain taxonomy in a reliable and stable manner. Here, a N. gonorrhoeae genomic lineage nomenclature, based on the barcoding system of Life Identification Number (LIN) codes, was developed using a refined 1430 core gene MLST (cgMLST). This hierarchical LIN code nomenclature conveys lineage information at multiple levels of resolution within one code, enabling it to provide immediate context to an isolate’s ancestry, and to relate to familiar, previously used typing schemes such as Ng cgMLST v1, 7-locus MLST, or NG-STAR clonal complex (CC). Clustering with LIN codes accurately reflects gonococcal diversity and population structure, providing insight into associations between genotype and phenotype for traits such as antibiotic resistance. These codes are automatically assigned and publicly accessible via the https://pubmlst.org/organisms/neisseria-spp database.