PLoS Genet. [JOURNAL]
Sun
200 papers
Zebrafish genetic model of neuromuscular degeneration associated with Atrogin-1 expression.
Menard R, Morin E, Morse D … +15 more , Halluin C, Pende M, Baanannou A, Grendler J, Fuqua H, Li J, Lancelot L, Drent J, Bonnet F, Graber JH, Murawala P, Dray C, Pradère JP, Coffman JA, Madelaine R
PLoS Genet · 2026 Jan · PMID 41511973 · Full text
The degenerative loss of muscle associated with aging leading to muscular atrophy is called sarcopenia. Currently, practicing regular physical exercise is the only efficient way to delay sarcopenia onset. Identification...
The degenerative loss of muscle associated with aging leading to muscular atrophy is called sarcopenia. Currently, practicing regular physical exercise is the only efficient way to delay sarcopenia onset. Identification of therapeutic targets to alleviate the symptoms of aging requires in vivo model organisms of accelerated muscle degeneration and atrophy. The zebrafish undergoes aging, with hallmarks including mitochondrial dysfunction, telomere shortening, and accumulation of senescent cells. However, zebrafish age slowly, and no specific zebrafish models of accelerated muscle atrophy associated with molecular events of aging are currently available. We have developed a new genetic tool to efficiently accelerate muscle-fiber degeneration and muscle-tissue atrophy in zebrafish larvae and adults. We used a gain-of-function strategy with a molecule that has been shown to be necessary and sufficient to induce muscle atrophy and a sarcopenia phenotype in mammals: Atrogin-1 (also named Fbxo32). We report the generation, validation, and characterization of a zebrafish genetic model of accelerated neuromuscular atrophy, the atrofish. We demonstrated that Atrogin-1 expression specifically in skeletal muscle tissue induces a muscle atrophic phenotype associated with locomotion dysfunction in both larvae and adult fish. We identified degradation of the myosin light chain as an event occurring prior to muscle-fiber degeneration. Biological processes associated with muscle aging such as proteolysis, inflammation, stress response, extracellular matrix (ECM) remodeling, and apoptosis are upregulated in the atrofish. Surprisingly, we observed a strong correlation between muscle-fiber degeneration and reduced numbers of neuromuscular junctions in the peripheral nervous system, as well as neuronal cell bodies in the spinal cord, suggesting that muscle atrophy could underly a neurodegenerative phenotype in the central nervous system. Finally, while atrofish larvae can recover locomotive functions, adult atrofish have impaired regenerative capacities, as is observed in mammals during muscle aging. In the future, the atrofish could serve as a platform for testing molecules aimed at treating or alleviating the symptoms of muscle aging, thereby opening new therapeutic avenues in the fight against sarcopenia.
Genomic profiling of active vitamin D colonic responses in African- and European-Americans identifies an ancestry-related regulatory variant of POLB.
Witonsky D, Laxman B, Usman H … +3 more , Bielski MC, Lawrence KM, Kupfer SS
PLoS Genet · 2026 Jan · PMID 41505470 · Full text
We measured genomic responses to active vitamin D, 1α,25-dihydroxyvitamin D (1,25D), in colonic organoids from individuals of African and European ancestry. Given protective effects of 1,25D for gastrointestinal conditio...
We measured genomic responses to active vitamin D, 1α,25-dihydroxyvitamin D (1,25D), in colonic organoids from individuals of African and European ancestry. Given protective effects of 1,25D for gastrointestinal conditions such as colorectal cancer, organoid cultures enabled evaluation of condition-specific responses in relevant target tissue across individuals of diverse ancestries. We found significant alterations in transcriptional and chromatin accessibility responses to 1,25D treatment, including some with ancestry-associated differences, and also elucidated the role of cis-genetic variants on treatment responses. Integration of genomic profiling with genetic mapping found an insertion-deletion variant that explains ancestry-associated differences in 1,25D regulation of POLB, an oxidative DNA repair enzyme involved in colorectal carcinogenesis, which also showed signals of positive natural selection. These findings highlight the importance of including diverse individuals in functional genomics studies to identify potential drivers of population-level differences relevant for clinical outcomes, and to uncover functional mechanisms that may be obscured by ancestry variation.
CaZAT5 delays the flowering time in tomato and affects pollen viability and anther dehiscence.
Xiao J, Yang M, Yang J … +7 more , Tang W, Song X, Tang Y, Sun B, Zheng Y, Huang Z, Li H
PLoS Genet · 2026 Jan · PMID 41494030 · Full text
Male sterility (MS) plays a crucial role in plant reproduction and hybrid breeding as it is associated with pollen viability and release. However, the regulatory mechanisms governing anther dehiscence in peppers remain p...
Male sterility (MS) plays a crucial role in plant reproduction and hybrid breeding as it is associated with pollen viability and release. However, the regulatory mechanisms governing anther dehiscence in peppers remain poorly characterized. Thus, this study identified the pepper C2H2 family transcription factor CaZAT5 and characterized its function. The results indicated that CaZAT5 represses transcriptional activity and is predominantly expressed during pepper flower development. Silencing CaZAT5 in pepper led to early flowering, whereas its overexpression (OE) in tomato delayed flowering. Moreover, CaZAT5 negatively regulated vegetative growth by suppressing CaSOC1 expression, thereby affecting pollen morphology and viability. Histological analyses revealed that the anthers of CaZAT5-OE plants exhibited abnormal mitosis, resulting in both enlarged and shrunken pollen grains. Additionally, CaZAT5 overexpression inhibited anther dehiscence during pollen maturation, affecting pollen release. The consequent reduction in pollen viability and inhibited anther dehiscence decreased fruit set and yield in the plants. Transcriptome (RNA-seq) analysis revealed that CaZAT5 overexpression suppressed the expression of genes involved in cell wall loosening, degradation, and secondary wall thickening in the anthers. DAP-seq, Y1H, Dual-LUC, and EMSA identified potential CaZAT5-regulated genes involved in anther dehiscence, including cell wall degradation genes (CaPG and CaBG4) and the expansin gene CaExpA13. Collectively, these findings suggest that CaZAT5 modulates flowering time, pollen development, and anther dehiscence by regulating the expression of genes related to flowering and cell wall loosening and degradation. These findings contribute to a more comprehensive understanding of the potential role of CaZAT5 in regulating flowering time and male fertility.
Cosmopolitan inversions have a major impact on trait variation and the power of different GWAS approaches to identify associations.
Lenhart BA, Bergland AO
PLoS Genet · 2026 Jan · PMID 41490148 · Full text
The ability of genomic inversions to reduce recombination and generate linkage can have a major impact on genetically based phenotypic variation in populations. However, the increase in linkage associated with inversions...
The ability of genomic inversions to reduce recombination and generate linkage can have a major impact on genetically based phenotypic variation in populations. However, the increase in linkage associated with inversions can create hurdles for identifying associations between loci linked to inversions and the traits they impact. Therefore, the role of inversions in mediating genetic variation of complex traits remains to be fully understood. This study uses the fruit fly Drosophila melanogaster to investigate the impact of inversions on trait variation. We tested the effects of common inversions among a diverse assemblage of traits including aspects of behavior, morphology, and physiology, and identified that the cosmopolitan inversions In(2L)t and In(3R)Mo are associated with many traits. We compared the ability of different approaches of accounting for relatedness and inversion presence during genome-wide association to identify signals of association with SNPs. We report that commonly used association methods are underpowered within inverted regions, while alternative approaches such as leave-one-chromosome-out improve the ability to identify associations. In all, our research enhances our understanding of inversions as components of trait variation and provides insight into approaches for identifying genomic regions driving these associations.
Sex-specific functional evolution of Dmrt1 in African clawed frogs (Xenopus), and the importance of genetic tipping points in developmental biology.
Kukoly LM, Porter SR, Jordan DC … +8 more , Murphy HA, Knytl M, Shaidani N, Thomas WR, Anderson C, Dworkin I, Horb ME, Evans BJ
PLoS Genet · 2026 Jan · PMID 41481615 · Full text
The doublesex and mab-3 related transcription factor 1 (dmrt1) plays a crucial role in metazoan sexual differentiation. This gene, or its paralogs, independently became triggers for sex determination several times, inclu...
The doublesex and mab-3 related transcription factor 1 (dmrt1) plays a crucial role in metazoan sexual differentiation. This gene, or its paralogs, independently became triggers for sex determination several times, including in the tetraploid African clawed frog Xenopus laevis. To explore functional evolution of this gene, we generated knockout lines of each of two dmrt1 homeologs in X. laevis and an ortholog in the closely related diploid Western clawed frog X. tropicalis. Our findings evidence sex-specific functional evolution following duplication by allotetraploidization in an ancestor of X. laevis. In females, dmrt1 was essential for fertility and oogenesis in the Xenopus ancestor, but this important function was lost (subfunctionalized) in one X. laevis homeolog (dmrt1.S) after allotetraploidization. In males - in sharp contrast - dmrt1 was not essential for fertility and spermatogenesis in the Xenopus ancestor, but this essentiality was acquired (neofunctionalized) in the other X. laevis homeolog (dmrt1.L) after allotetraploidization. Transcriptomic analysis of the mesonephros/gonad complex during sexual differentiation identifies distinctive patterns of dysregulation in male and female knockouts of dmrt1.L and dmrt1.S relative to same-sex wildtype siblings, including possible autocatalysis of dmrt1.L and activation of the female-determining gene dm-w. Previous work demonstrates that dm-w was recently derived from partial gene duplication of dmrt1.S - a gene that our analysis demonstrates is non-essential in both sexes. Thus, in X. laevis, a developmental system was pushed past a "tipping point" to a novel state where sexual differentiation is now orchestrated by a sex-specific duplicate of a dispensable gene.
Lack of ANKMY2 suppresses kidney cystogenesis in embryonic- and adult-onset polycystic kidney disease.
Hwang SH, Choi K, Badgandi H … +5 more , White KA, Xun Y, Woodward OM, Qian F, Mukhopadhyay S
PLoS Genet · 2025 Dec · PMID 41474822 · Full text
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive bilateral cyst formation. Multiple cellular pathways including second messenger cAMP signaling are dysregulated in ADPKD, but mechanism...
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive bilateral cyst formation. Multiple cellular pathways including second messenger cAMP signaling are dysregulated in ADPKD, but mechanisms initiating cysts are unknown. ADPKD is caused by mutations in PKD1/PKD2 genes encoding for polycystins that localize to primary cilia-nonmotile, microtubule-based dynamic compartments sensing extracellular chemical/mechanical signals. The compact cylindrical structure of cilia enables tunable signaling amplification regulatable by ciliary length. Severe cystogenesis from polycystin loss is cilia dependent and ciliary elongation is common in cystic epithelia. However, uncoupling the cilium-specific signals repressed by polycystins from downstream cystogenic pathways has proven challenging. Here we aim to understand roles of compartmentalized cAMP signaling in cystogenesis and ciliary length control. We investigated ANKMY2, an Ankyrin repeat MYND domain protein involved in maturation and ciliary localization of membrane adenylyl cyclases-enzymes generating cAMP. In kidney-specific Ankmy2/Pkd1 knockout mice, loss of ANKMY2 suppressed early postnatal cystogenesis and significantly extended survival in an embryonic-onset Pkd1 deletion model. Similarly, in an adult inducible Pkd1 knockout model, ANKMY2 deficiency reduced cyst burden. Mechanistically, ANKMY2 controlled the ciliary trafficking of multiple adenylyl cyclases in mouse and human kidney epithelial cells without disrupting cilia while retaining cellular pools. Ciliary elongation began in dilatated tubules of adult onset ADPKD mice and further increased in cystic kidneys. Both initial and progressive phases of cilia lengthening were ANKMY2-dependent. Our findings indicate that ciliary adenylyl cyclase signaling likely promotes cilia-dependent cyst initiation distinct from cyst progression involving cellular cAMP. Importantly, kidneys lacking ANKMY2 did not show ciliary elongation despite elevated cAMP, suggesting that cilia lengthening during cyst progression could be contingent upon pre-cystic ciliary regulation. These results suggest a critical role for compartmentalized adenylyl cyclase signaling in ADPKD pathogenesis and a framework for identifying ciliary effectors and early subcellular events in cystogenesis.
A maize mutant in the glutamate receptor-like dwarf13 is modified by cis-acting natural variation and a cornichon homolog.
Kaur A, Khangura RS, Dilkes BP
PLoS Genet · 2025 Dec · PMID 41474800 · Full text
Deciphering the molecular basis of complex traits requires understanding how natural genetic variation interacts with underlying biological pathways. In this study, we explored how natural genetic variation influences tr...
Deciphering the molecular basis of complex traits requires understanding how natural genetic variation interacts with underlying biological pathways. In this study, we explored how natural genetic variation influences traits in maize affected by a semi-dominant maize dwarfing allele, Dwarf13-1 (D13-1) which encodes a defective ionotropic glutamate receptor (GLR). This allowed us to investigate natural genetic variation in the genome affecting GLR signaling in maize. We implemented an F1 association mapping (FOAM) approach, where heterozygous mutants carrying the semi-dominant D13-1 allele were crossed with a maize association panel. The resulting F1 families segregated 1:1 for mutant and wild-type phenotypes allowing comparisons between the congenic F1 hybrid siblings to identify and map natural alleles that interact with the D13-1 mutant allele. FOAM mapping detected two loci that modify the expression of the D13-1/+ mutant phenotype. The phenotypic impacts of both loci were epistatically controlled by D13-1, and only affected the phenotypes of mutant F1 hybrids. One, tropotriskaideka1 (tod1), encoded a maize homolog of the GLR-interacting cornichon gene and modified D13-1/+ mutant severity. A second, encoded by the d13 locus itself, affected the severity of the D13-1/+ phenotype via variation in the wild-type allele in the heterozygous mutants. By integrating gene expression analyses, these epistatic interactions, and SNP linkage information we identified multiple, unlinked, alleles affecting expression of the wild-type D13 transcript that modify mutant trait expression. Greater expression of the wild-type D13 allele increased plant height and suppressed D13-1/+ mutant severity, consistent with a multi-subunit complex GLR structure and complex-poisoning mode-of-action for the semi-dominant D13-1 allele. This approach identifies natural alleles affecting the GLR pathway in maize and establishes GLRs and their interactors as dose-dependent regulators of plant architecture. Our pathway-focused framework and epistasis testing of natural variants provides greater confidence in identifying genes contributing to complex traits.
Modulators of gene amplification alter evolution of antibiotic resistance in Staphylococcus aureus.
Silva KPT, Martini AM, Khare A
PLoS Genet · 2025 Dec · PMID 41474795 · Full text
Gene amplification is thought to be common in bacterial populations, providing a rapid and reversible mode of adaptation to diverse stresses, including the acquisition of antibiotic resistance. We previously showed that...
Gene amplification is thought to be common in bacterial populations, providing a rapid and reversible mode of adaptation to diverse stresses, including the acquisition of antibiotic resistance. We previously showed that the opportunistic pathogen Staphylococcus aureus evolves resistance to the dual-targeting fluoroquinolone delafloxacin (DLX) that inhibits both the DNA gyrase and DNA topoisomerase IV via amplification of an efflux pump encoding gene sdrM. However, the pathways that control gene amplification, and consequently adaptive trajectories, remain understudied, especially in gram-positive bacteria like S. aureus. Here, we show that specific DNA repair and chromosomal separation proteins alter the frequency of gene amplification and selection of amplified regions in S. aureus. Through a screen of 40 mutants deficient in various DNA processes, we determined that while sdrM amplification was still the almost universal path to DLX resistance, other mutations that increased sdrM expression reduced the selection frequency of sdrM amplification, demonstrating the critical role of sdrM in DLX resistance. We found that similar to other bacteria, both sdrM amplification and loss of amplified gene copies required a functional RecA recombinase, but multiple other mutants in pathways required for amplification in other species still exhibited frequent sdrM amplification, suggesting that S. aureus may have alternate routes of gene amplification. Finally, loss of function mutants of the tyrosine recombinase XerC, that is known to play a role in chromosomal separation, were deficient for sdrM amplification, indicating that XerC is a novel modulator of gene amplification, or the maintenance or selection of amplified gene copies. Thus, our work sheds light on genetic factors that alter gene amplification-mediated evolutionary trajectories to antibiotic resistance in S. aureus and can potentially unlock mechanisms by which such evolution of resistance can be inhibited.
Huntington's disease-associated ankyrin repeat palmitoyl transferases are rate-limiting factors in lysosome formation and fusion.
Szenci G, Boda A, Nagy A … +8 more , Károlyi D, Rubics A, Szőke Z, Falcsik G, Kovács T, Lőrincz P, Juhász G, Takáts S
PLoS Genet · 2025 Dec · PMID 41474785 · Full text
Protein palmitoylation in the Golgi apparatus is critical for the appropriate sorting of various proteins belonging to secretory and lysosomal systems, and defective palmitoylation can lead to the onset of severe patholo...
Protein palmitoylation in the Golgi apparatus is critical for the appropriate sorting of various proteins belonging to secretory and lysosomal systems, and defective palmitoylation can lead to the onset of severe pathologies. HIP14 and HIP14L ankyrin repeat-containing palmitoyl transferases were linked to the pathogenesis of Huntington's disease, however, how perturbation of these Golgi resident enzymes contributes to neurological disorders is yet to be understood. In this study, we investigated the function of Hip14 and Patsas - the Drosophila orthologs of HIP14 and HIP14L, respectively - to uncover their role in secretory and lysosomal membrane trafficking. Using larval salivary gland, a well-established model of the regulated secretory pathway, we found that these PAT enzymes equally contribute to the proper maturation and crinophagic degradation of glue secretory granules by mediating their fusion with the endo-lysosomal compartment. We also revealed that Patsas and Hip14 are both required for lysosomal acidification and biosynthetic transport of various lysosomal hydrolases, and we demonstrated that the rate of secretory granule-lysosome fusion and subsequent acidification positively correlates with the level of Hip14. Furthermore, Hip14 is also essential for proper lysosome morphology and neuronal function in adult brains. Finally, we found that the over-activation of lysosomal biosynthetic transport and lysosomal fusions by the expression of the constitutively active form of Rab2 could compensate for the lysosomal dysfunction caused by the loss of Patsas or Hip14 both in larval salivary glands and neurons. Therefore, we propose that ankyrin repeat palmitoyl transferases act as rate-limiting factors in lysosomal fusions and provide genetic evidence that defective protein palmitoylation and the subsequent lysosomal dysfunction can contribute to the onset of Huntington's disease-like symptoms.
A new regulator of the Staphylococcus aureus peptidoglycan hydrolase Sle1.
Veiga H, Izquierdo-Martinez A, Marques LB … +1 more , Pinho MG
PLoS Genet · 2025 Dec · PMID 41474740 · Full text
Regulation of peptidoglycan hydrolases is crucial for bacterial cell integrity, growth and division. In the bacterial pathogen Staphylococcus aureus, the amidase Sle1 is a key autolysin required for septum splitting and...
Regulation of peptidoglycan hydrolases is crucial for bacterial cell integrity, growth and division. In the bacterial pathogen Staphylococcus aureus, the amidase Sle1 is a key autolysin required for septum splitting and daughter cell separation. Through genetic suppressor screening, we have identified CxaR, a previously uncharacterized protein, as a novel negative regulator of Sle1. In the absence of CxaR, cellular levels of Sle1 increase nearly ten-fold, resulting in premature splitting of the division septum and increased cell lysis during exponential growth. CxaR localizes to the division septum, late in septum synthesis, and this localization requires both the divisome protein FtsK and the ClpX component of the ClpXP proteolytic machinery. We propose that CxaR promotes ClpXP-mediated degradation of Sle1 towards the end of the cell cycle.
Getting to GRIPS with MR-Egger: Modelling directional pleiotropy independently of allele coding.
Dudbridge F, Voller B, Woodward RM … +4 more , Saxby KL, Frayling TM, Pilling LC, Bowden J
PLoS Genet · 2025 Dec · PMID 41468517 · Full text
Mendelian Randomisation Egger regression (MR-Egger) is a popular method for causal inference using single-nucleotide polymorphisms (SNPs) as instrumental variables. It allows all SNPs to have direct pleiotropic effects o...
Mendelian Randomisation Egger regression (MR-Egger) is a popular method for causal inference using single-nucleotide polymorphisms (SNPs) as instrumental variables. It allows all SNPs to have direct pleiotropic effects on the outcome, provided that those effects are independent of the effects on the exposure, known as the InSIDE assumption. However, the results of MR-Egger, and the InSIDE assumption itself, are sensitive to which allele is coded as the effect allele for each SNP. A pragmatic convention is to code the alleles with positive effects on the exposure, which has some advantages in interpretation but some statistical limitations. Here we show that if the InSIDE assumption holds under all-positive coding of the exposure effects, it cannot hold under all-positive coding of the pleiotropic effects, and argue that this undermines the soundness of MR-Egger. We propose a modification that has the Genotype Recoding Invariance Property (GRIP), achieving the main aim of MR-Egger without the difficulties of allele coding. Our approach, MR-GRIP, is valid under a "Variance Independent of Covariance Explained" assumption (VICE), which amounts to an inverse relationship between exposure effects and pleiotropic effects. Examples and simulations suggest that MR-GRIP can reconcile differences between MR-Egger and alternative methods.
Decoding the germline genetic architecture of prostate cancer at a single cell resolution.
Wang C, Tang T, Wang Y … +1 more , Li J
PLoS Genet · 2025 Dec · PMID 41468516 · Full text
Prostate cancer exhibits a strong familial association, and its heritability indicates a significant contribution from germline variants. While genome-wide association studies (GWAS) have identified common germline varia...
Prostate cancer exhibits a strong familial association, and its heritability indicates a significant contribution from germline variants. While genome-wide association studies (GWAS) have identified common germline variants associated with prostate cancer risk, translating these statistical associations into functional mechanisms has remained a long-standing challenge. Consequently, most of our understanding of the genetic basis of prostate cancer stems from extensive studies of somatic mutations, leaving the germline genetic architecture largely unresolved. Because most germline variants lie in the noncoding genome and complex human diseases are predominantly driven by regulatory mutations, we herein asked which prostate cell types mediate the functional effects of germline variants, and thus represent the most genetically vulnerable populations. We generated paired epigenomic and transcriptomic profiles from reference human prostate tissues. Integrating these single-cell data with large-scale GWAS data identified a terminally differentiated luminal epithelial subtype that mediates the strongest germline risk in prostate cancer. We subsequently developed a deep learning model to score ~17 million GWAS variants based on their predicted impact on altering local chromatin accessibility in this vulnerable luminal epithelial subtype, and identified high-confidence candidate loci where high-risk germline variants likely alter promoter accessibility in prostate cancer. The implicated genes were involved in several pathways in tumorigenesis, displayed strong dosage sensitivity, and converged on the androgen receptor (AR)-mediated regulon, a mechanism also observed for somatic mutations. Overall, by unveiling cell types and candidate loci that mediate germline risk, our study defines the cell-type-specific germline architecture in prostate cancer and provides a comprehensive framework for understanding cancer heritability.
LINE-1 retrotransposition in a mouse TDP-43 model of neurodegeneration marks motor cortex neurons for cell-intrinsic and cell non-autonomous programmed cell death.
Korada S, Tam OH, Greco HC … +3 more , Hammell MG, Dubnau J, Sher RB
PLoS Genet · 2025 Dec · PMID 41460923 · Full text
A key pathological feature of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) is the loss of nuclear localization and accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43). T...
A key pathological feature of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) is the loss of nuclear localization and accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43). TDP-43 is a nucleic acid-binding protein involved in transcriptional repression, mRNA splicing, and the regulation of retrotransposable elements (RTEs) and endogenous retroviruses (ERVs). RTEs/ERVs are mobile virus-like genetic elements that constitute about 45% of our genome and encode the capacity to replicate through an RNA intermediate and insert cDNA copies at de novo chromosomal locations. A causal role of RTEs/ERVs has been demonstrated in Drosophila in mediating both intracellular toxicity of TDP-43 and the intercellular spread of toxicity from glia to neurons. RTEs/ERVs are inappropriately expressed in postmortem tissues from ALS, FTD, and Alzheimer's Disease (AD) patients, but the role of RTEs/ERVs has not yet been examined in a vertebrate model of TDP-43 pathology. We utilized established transgenic mouse models that overexpress moderate levels of human wild-type TDP-43 or a mutant version with a specific ALS-causal Q331K amino acid substitution, together with a LINE-1-EGFP retrotransposon indicator line. We found that TDP-43 animals exhibit broad expression of RTEs/ERVs with LINE-1 retrotransposition in glia and neurons in the motor cortex. Expression begins with onset of neurological phenotypes, earlier in hTDP-43-Q331K animals and later in hTDP-43-WT. The LINE-1-EGFP retrotransposition reporter transiently labels spatially clustered groups of neurons and glia at the time of onset of motor symptoms, while EGFP-labeled neurons undergo cell death and are therefore lost over time. Unlabeled cells also die as a function of distance from the clusters of LINE-1-EGFP labeled neurons and glial cells. Together, these findings support the hypothesis that TDP-43 pathology triggers RTE/ERV expression in the motor cortex, that such expression marks cells for programmed cell death, with cell non-autonomous effects on nearby neurons and glial cells.
The TRP-channel painless mediates substrate stiffness sensing in the legs during Drosophila oviposition.
Ray V, Bräcker LB, Kourtidis A … +7 more , Rosher C, Dinges GF, Pierzchlińska A, Büschges A, Feng K, Cury KM, Gompel N
PLoS Genet · 2025 Dec · PMID 41460914 · Full text
The distinct textural properties of fruits in varying stages of ripening present unique ecological opportunities for several species of fruit flies, resulting, over evolutionary times, in specialized egg-laying behaviors...
The distinct textural properties of fruits in varying stages of ripening present unique ecological opportunities for several species of fruit flies, resulting, over evolutionary times, in specialized egg-laying behaviors. In this study we identified a TrpA channel-dependent mechanosensory pathway in the legs, through the gene painless, that modulates the discernment of softer patches for oviposition in gravid D. melanogaster females. We report that the stiffness-sensing role of tarsi is mediated through external sensory organs, namely ventral mechanosensory bristles and subsets of campaniform sensilla present primarily at the joints between tarsomeres. Our findings provide new evidence that campaniform sensilla function as indirect stiffness sensors of oviposition substrates, owing to their placement at joints that experience maximal cuticular distortion. We show that Painless is expressed in mechanosensory neurons innervating peripheral organs and is necessary for their functions in mediating oviposition substrate selection in gravid females. Furthermore, we observed that overexpression of painless in both campaniform sensilla and mechanosensory bristles partially rescues preference for the softer substrates in painless mutants, indicating that painless activity in these organs is necessary to mediate the preference. We propose that different interactions with a soft vs. a hard substrate (compression of the cuticle, distribution of contacts) results in differential mechanotransduction in painless-expressing neurons, determining oviposition preferences.
A toxin/antitoxin system targeting the replication sliding-clamp induces competence in Streptococcus pneumoniae.
Maziero M, Juillot D, Mortier-Barrière I … +6 more , Carballido-Lopez R, Campo N, Genevaux P, Bordes P, Polard P, Bergé M
PLoS Genet · 2025 Dec · PMID 41460877 · Full text
Streptococcus pneumoniae is a pathogenic bacterium capable of entering a cellular differentiation state, called competence, which enables it to acquire new genetic functions by natural transformation, as well as physiolo...
Streptococcus pneumoniae is a pathogenic bacterium capable of entering a cellular differentiation state, called competence, which enables it to acquire new genetic functions by natural transformation, as well as physiological functions such as tolerance to a number of antibiotics. The transition to this state is regulated by various environmental or intracellular signals that converge on the comCDE operon, which groups together the competence initiation genes. A fraction of activated cells is sufficient to propagate competence to the whole population via the product of the comC gene, the competence stimulating peptide (CSP). Remarkably, depletion of the essential ClpX/ ClpP AAA+ protease has been shown to induce the comCDE operon. Here we demonstrate that the ClpX-dependent induction of competence relies on the Spr1630 toxin (RipA), part of a Rosmer toxin-antitoxin system. We show that this toxin generates replicative stress by acting on the sliding clamp of replication, inducing transcription of the comCDE operon. Bacteria that produce RipA appear to lose their viability but remain metabolically active and able to produce CSP, thereby transferring competence to viable neighbouring cells.
Chinmo function in cockroaches provides new insights into the regulation and evolution of insect metamorphosis.
Escudero J, Gonzalvo J, Piulachs MD … +1 more , Belles X
PLoS Genet · 2025 Dec · PMID 41452921 · Full text
Insect metamorphosis occurs in two main forms, hemimetaboly (simple) and holometaboly (complete), both regulated by hormonal and genetic pathways involving the transcription factors Krüppel homolog 1 (Kr-h1), Broad-Compl...
Insect metamorphosis occurs in two main forms, hemimetaboly (simple) and holometaboly (complete), both regulated by hormonal and genetic pathways involving the transcription factors Krüppel homolog 1 (Kr-h1), Broad-Complex (BR-C), and Ecdysone-induced protein 93F (E93). The BTB-zinc finger protein Chronologically inappropriate morphogenesis (Chinmo), recently identified in the fruit fly Drosophila melanogaster, an holometabolan, as a larval state maintainer, was studied here in the German cockroach, Blattella germanica, an hemimetabolan. We also examined another BTB transcription factor, Abrupt (Ab), based on findings in another holometabolan, the red flour beetle, Tribolium castaneum, suggesting a cooperative role. We characterized chinmo expression in B. germanica and found sustained transcript levels during the N4 and N5 nymphal instars, followed by a marked decline at the final N6 instar. RNA interference (RNAi) knockdown of chinmo at N4 induced precocious metamorphosis two molts later, accompanied by reduced Kr-h1 and elevated E93 expression. Combined knockdown of chinmo and E93 revealed that Chinmo primarily represses E93. Similarly, ab knockdown also triggered precocious metamorphosis, decreasing Kr-h1 and increasing E93 expression; double knockdown of ab and E93 indicated that Ab primarily promotes Kr-h1 expression. These results expand the MEKRE93 pathway by identifying Chinmo and Ab as additional regulators that help maintain the juvenile state in both hemimetabolan and holometabolan insects. Holometaboly likely evolved from hemimetabolan ancestors through the embryonic internalization of wing primordia into imaginal cells, which enabled the emergence of distinct larval forms. Key regulatory factors like Kr-h1, Chinmo, Ab, BR-C, and E93, already present in hemimetabolan lineages, were conserved and rewired in holometabolans. Crucial shifts in this evolutionary transition include Chinmo-mediated inhibition of BR-C and an inversion in the juvenile hormone effect on BR-C, from activation to repression.
Crosstalk between cohesins and axis proteins determines meiotic chromosome architecture in Sordaria macrospora.
Yefsah K, Habbi M, Budin K … +4 more , Bourbon HM, Zickler D, Espagne E, Boisnard S
PLoS Genet · 2025 Dec · PMID 41433359 · Full text
Faithful chromosome segregation during meiosis requires the coordinated action of cohesin complexes and chromosome axis proteins. How these factors interact and communicate along chromosome axes, especially during meioti...
Faithful chromosome segregation during meiosis requires the coordinated action of cohesin complexes and chromosome axis proteins. How these factors interact and communicate along chromosome axes, especially during meiotic prophase I, remains however, only partially understood. We therefore investigated the functional interplay between the cohesin components and regulators (Rad21, Rec8, Wapl, Sororin, Spo76/Pds5) and two meiosis-specific axis proteins Red1 and Hop1. Analysis of multiple combinations of their corresponding null mutants and of their genetic-epistasis interactions in the fungus Sordaria macrospora revealed a hierarchical regulatory network for their recruitment and releasing. This work uncovers an unexpected role of axis proteins Red1 and Hop1, that together with Sororin, provide stage-specific protection of Spo76/Pds5 against Wapl-mediated release. Furthermore, we identify that Spo76/Pds5 is the main target of Wapl and acts as a central guardian of kleisin stability against Slx8/STUbL-dependent proteasomal degradation. Together, our findings show that dynamic crosstalk between axis proteins and cohesins is crucial to preserve axis integrity and to ensure accurate meiotic progression.
Histone lactylation: A new epigenetic mark in the malaria parasite Plasmodium.
Jabre I, Andoh NE, Naldoni J … +7 more , Gregory W, Mbye H, Yoon CE, Cunnington AJ, Georgiadou A, Blagborough AM, Merrick CJ
PLoS Genet · 2025 Dec · PMID 41417877 · Full text
Epigenetic processes play important roles in the biology of the malaria parasite Plasmodium falciparum. Here, we characterised a new epigenetic mark, histone lactylation, for the first time in Plasmodium: it was found in...
Epigenetic processes play important roles in the biology of the malaria parasite Plasmodium falciparum. Here, we characterised a new epigenetic mark, histone lactylation, for the first time in Plasmodium: it was found in two human malaria parasites, P. falciparum and P. knowlesi, and also in vivo in two rodent malaria models, P. yoelii and P. berghei. Histones were increasingly lactylated in response to elevated lactate levels in vitro and in vivo, making this mark uniquely well-placed to act as a metabolic sensor, since severe falciparum malaria characteristically leads to hyperlactataemia in the human host. Mass spectrometry showed that lysines on several parasite histones could be lactylated, as well as many non-histone chromatin proteins. Histone lactylation was less abundant and less inducible in P. knowlesi than P. falciparum, suggesting that P. falciparum may have evolved particular epigenetic responses to this characteristic feature of its pathology. Finally, in the rodent model P. yoelii, hyperlactataemia correlated with parasite transcriptomic programmes that suggested metabolic 'dormancy'.
A simple method to efficiently generate structural variation in plants.
Bechen LL, Ahsan N, Bahrainwala A … +2 more , Gehring M, Satyaki PRV
PLoS Genet · 2025 Dec · PMID 41411371 · Full text
Phenotypic variation is essential for the selection of new traits of interest. Structural variants, consisting of deletions, duplications, inversions, and translocations, have greater potential for phenotypic consequence...
Phenotypic variation is essential for the selection of new traits of interest. Structural variants, consisting of deletions, duplications, inversions, and translocations, have greater potential for phenotypic consequences than single nucleotide variants. Pan-genome studies have highlighted the importance of structural variation in the evolution and selection of novel traits. Here, we describe a simple method to induce structural variation in plants. We demonstrate that a short period of growth on the topoisomerase II inhibitor etoposide induces heritable structural variation and altered phenotypes in Arabidopsis thaliana at high frequency. Using long-read sequencing and genetic analyses, we identified deletions and inversions underlying semi-dominant and recessive phenotypes. This method requires minimal resources, is potentially applicable to any plant species, and can replace irradiation as a source of induced large-effect structural variation.
Circular RNA profiling revealed an evolutionarily conserved circACACA promotes liver lipid metabolism, oxidative stress, and autophagy disorder in a ceRNA manner.
Zhao J, Han S, Xiang J … +7 more , Chen Y, Zhao X, Wang W, Zhang Y, Zhu Q, Liu C, Yin H
PLoS Genet · 2025 Dec · PMID 41411370 · Full text
Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized primarily by hepatocellular steatosis and lipid accumulation, which leads to hepatocyte apoptosis, autophagy, inflammation, and intracellular...
Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized primarily by hepatocellular steatosis and lipid accumulation, which leads to hepatocyte apoptosis, autophagy, inflammation, and intracellular oxidative stress. NAFLD is recognized as one of the most prevalent and complex chronic liver diseases globally, with its occurrence and associated mortality rates rising swiftly each year. Due to the high similarity between chicken fatty liver syndrome (FLS) and NAFLD, as well as the easy availability of diseased chickens, the chicken is considered an ideal model for studying the pathogenesis of NAFLD. Previous studies have pinpointed several circular RNAs (circRNAs) implicated in the pathogenesis of NAFLD, yet the underlying functions and mechanisms of numerous circRNAs continue to remain elusive. In this experiment, we utilized circRNA sequencing of chicken livers to identify a novel circRNA, named circACACA, and discovered that it disrupts the metabolic homeostasis of lipids within hepatocytes. Consequently, this disruption leads to oxidative stress and the induction of autophagy, ultimately exerting an adverse effect on chicken liver health. Mechanistically, circACACA functions as a molecular sponge for miR-132b-5p and miR-101-2-5p to modulate the expression of the downstream CBFB/PIM1 complex. Consequently, it influenced the activity of the AKT/mTOR and PPAR-γ signaling pathways to perform its physiological functions. Crucially, we noticed substantial sequence similarity of circACACA across diverse species by comprehensively searching databases. Further, our research with a mouse model confirmed that the functional conservation of circACACA across livers of different species. Overall, this study built a mechanistic network for circACACA and confirmed its sequence conservation and functional relevance across various species. Our results not only provide new targets for the prevention and treatment of NAFLD but also present fresh perspectives for progress in healthy production of laying hens.
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