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Correction: DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma.
Ma RK, Tsai PY, Farghli AR … +11 more , Shumway A, Kanke M, Gordan JD, Gujral TS, Vakili K, Nukaya M, Noetzli L, Ronnekleiv-Kelly S, Broom W, Barrow J, Sethupathy P
PLoS Genet · 2026 Feb · PMID 41746900 · Full text
[This corrects the article DOI: 10.1371/journal.pgen.1011216.].
[This corrects the article DOI: 10.1371/journal.pgen.1011216.].
Combined mutations of hoxa13a, hoxa13b, and hoxd13a lead to structural shifts in zebrafish soft fin rays providing insight into spiny ray evolution.
Corcoran J, Quigley H, Qu Q … +1 more , Akimenko MA
PLoS Genet · 2026 Feb · PMID 41739864 · Full text
The zebrafish hoxa13a, hoxa13b, and hoxd13a genes have been shown to be essential for proper pectoral fin patterning. Combined mutations in these genes cause an elaboration of the pectoral fin endoskeleton, and a size re...
The zebrafish hoxa13a, hoxa13b, and hoxd13a genes have been shown to be essential for proper pectoral fin patterning. Combined mutations in these genes cause an elaboration of the pectoral fin endoskeleton, and a size reduction of the rays. In this study, we further examine the impact of partial deletions in these genes on the fin exoskeleton. Using morphological and micro-CT scan analyses, we found that rays of all fins of triple hox13 mutants are strongly affected, except for the caudal fin that is much less perturbed. Rays are shorter and thicker than wildtype rays, and present a loss of joints, bifurcations, and actinotrichia. Altogether, they lose many of the typical soft ray features and resemble more to the spiny rays of acanthomorphs. In these species, actinotrichia are present in spiny rays but organized differently than in soft rays, and spiny rays develop in the absence of hoxa13a/b expression. Gene expression analysis of triple hox13 mutant zebrafish larvae shows an expansion of the alx4a expression domain relative to the size of the dorsal and anal fin primordia and a reduction in grem1b expression that are reminiscent of the differences observed in acanthomorph spiny versus soft rays. Using various combinations of genotypes, hoxa13a and hoxa13b were found to be more important for normal soft ray formation than hoxd13a. In conclusion, our results demonstrate the importance of the hox13 paralogs for proper soft ray development and suggest a lack of hox13 expression could be important for their transformation into spiny rays.
The RPA-binding domain and the KKRK motif in Rad26ATRIP cooperate at the perturbed DNA replication fork for initiating checkpoint signalling.
Xu YJ, Gao A, Dev K … +5 more , Zheng Y, Alyahya MY, Pasam S, Kaur G, Zhou C
PLoS Genet · 2026 Feb · PMID 41729970 · Full text
Rad26 is the homolog of human ATRIP and budding yeast Ddc2 in Schizosaccharomyces pombe. Like ATRIP and Ddc2, Rad26 works with Rad3ATR/Mec1 to initiate checkpoint signalling in response to perturbed DNA replication and v...
Rad26 is the homolog of human ATRIP and budding yeast Ddc2 in Schizosaccharomyces pombe. Like ATRIP and Ddc2, Rad26 works with Rad3ATR/Mec1 to initiate checkpoint signalling in response to perturbed DNA replication and various types of DNA damage. To better understand the checkpoint initiation mechanism in fission yeast, we carried out genetic and biochemical analyses on the N-terminus of Rad26. Although Rad26 homologs do not share much sequence similarity, we demonstrate that, like ATRIP and Ddc2, Rad26 possesses a replication protein A (RPA) binding domain (RBD) in its N-terminus, suggesting a highly conserved mechanism. Elimination of the RBD in Rad26, however, only moderately affects the checkpoint signalling and cellular resistance to genotoxins. Rad26 has a short KKRK sequence in the N-terminal region, a motif conserved in Ddc2 that binds DNA and is crucial for the checkpoint function in budding yeast. Mutations of this motif in Rad26 cause only a minor defect in the checkpoint. However, simultaneous mutations of the RBD and the KKRK motif nearly eliminate the Rad3ATR kinase signalling at the perturbed replication fork. This suggests that the two functional units of Rad26 cooperate to initiate the DNA replication checkpoint. On the contrary, the simultaneous mutations of Rad26 only moderately or minimally sensitize the cell to different types of DNA damage. We hypothesize that the checkpoint initiation at the DNA damage site in fission yeast may follow a different mechanism that depends less on the two functional units of Rad26.
Loss of DNA mismatch repair genes leads to acquisition of antibiotic resistance independent of secondary mutations.
Bautista DE, Carr JF, Whitehead CR … +2 more , Kostoch B, Mitchell AM
PLoS Genet · 2026 Feb · PMID 41719364 · Full text
Antibiotic resistant bacteria have been a major clinical concern for decades. Beyond acquisition of alleles conferring resistance, bacteria under stress (e.g., from changing environmental conditions or mutations) can hav...
Antibiotic resistant bacteria have been a major clinical concern for decades. Beyond acquisition of alleles conferring resistance, bacteria under stress (e.g., from changing environmental conditions or mutations) can have higher intrinsic resistance to antibiotics than unstressed cells. This concern is expanded for gram-negative bacteria which have a protective outer membrane that serves as an additional barrier against harmful molecules such as antibiotics. Here, we report a pathway which increases antibiotic resistance (i.e., minimum inhibitory concentration) in response to inactivation of the DNA Mismatch Repair pathway (MMR). This pathway led to increased intrinsic resistance and was independent of secondary mutations. Specifically, deletion of the DNA mismatch repair genes mutL or mutS caused resistance to various antibiotics spanning different classes, molecular sizes, and mechanisms of action in several different E. coli K-12 MG1655 strains, and in Salmonella enterica serovar Typhimurium LT2. This pathway did not change outer membrane permeability or efflux rates. However, the patterns of resistance in MMR mutants correlated with previously reported increases in rates of homoeologous recombination (homologous recombination between non-identical DNA strands). Mutations expected to lower rates of recombination in MMR mutants also decreased the resistance to some antibiotics. Finally, we found lysis occurs in MMR mutants and may contribute to resistance. Our results have demonstrated a novel mechanism that increases antibiotic resistance in direct response to loss of MMR genes, and we propose this resistance involves increased rates of homoeologous recombination and cell lysis. The increased antibiotic resistance of MMR mutants provides a path for these cells to survive in antibiotics long enough to develop more specific resistance mutations and so may contribute to the development of new clinical resistance alleles.
Protein-interaction network analysis reveals the role of Prp19 splicing factor in transcription of both intron-containing and intron-lacking genes.
Dwyer K, Essak MA, Awada A … +2 more , Dhoondia Z, Ansari A
PLoS Genet · 2026 Feb · PMID 41719348 · Full text
The process of transcription and cotranscriptional mRNA processing are facilitated by myriads of molecular interactions. To elucidate the protein-protein interactions that occur during transcription cycle of RNAPII, we p...
The process of transcription and cotranscriptional mRNA processing are facilitated by myriads of molecular interactions. To elucidate the protein-protein interactions that occur during transcription cycle of RNAPII, we performed mass spectrometry of affinity purified termination complexes from chromatin fraction. Quantitative proteomic analysis revealed interaction of termination factors with TFIIB, TFIID and SAGA complex. Furthermore, all three termination complexes displayed statistically significant interactions with Prp19, Prp43, Sub2, Snu114, Brr2 and Smb1 splicing factors. Since Prp19 consistently emerged as the interactor of both initiation and termination complexes, we affinity-purified the factor and performed mass spectrometry. Prp19 exhibited interactions with subunits of TFIID, CPF complex, and the RSC chromatin remodeling complex. These interactions were observed exclusively in the chromatin context. Since fewer than 4% of yeast genes contain introns, we hypothesized that Prp19 might have a broader splicing-independent role in RNAPII transcription cycle. Auxin-mediated depletion of Prp19 resulted in at least a two-fold decrease in transcription of a subset of both intron-containing and intron-lacking genes. A combination of TFIIB-TBP ChIP and nascent RNA analyses revealed that Prp19 affects assembly of preinitiation complex (PIC) as well as termination step of transcription. Chromatin immunoprecipitation (ChIP) analysis revealed crosslinking of Prp19 to the promoter, coding region and terminator end of both intronic and non-intronic genes. These findings demonstrate that Prp19 has a novel role in transcription and affects multiple steps of RNAPII transcription cycle in budding yeast.
Genetic underpinnings of chills from art and music.
Bignardi G, Admiraal D, Eising E … +1 more , Fisher SE
PLoS Genet · 2026 Feb · PMID 41706705 · Full text
Art can evoke strong emotional responses in humans. Here, we examine genetic contributions to chills, a marker of such responses. We gather self-reports from a genotyped sample of thousands of partly related individuals...
Art can evoke strong emotional responses in humans. Here, we examine genetic contributions to chills, a marker of such responses. We gather self-reports from a genotyped sample of thousands of partly related individuals from the Netherlands (n = 15,606). Using genomic relationships based on common single-nucleotide polymorphism (SNP) data, we find that up to 29% of the variation in proneness to aesthetic (visual art and poetry) and music chills can be explained by familial relatedness effects, one-fourth of which is attributed to SNP variation. Furthermore, we reveal a moderate genetic correlation of .58 between aesthetic and music chills, pointing to shared genetic variation affecting susceptibility to strong emotional responses across different art forms. Finally, we find that a polygenic index (PGI) for openness to experience (n = 220,015) is associated with susceptibilities to both aesthetic and music chills. Our results show that additive genetic variation, but also familial relatedness beyond shared common SNPs, contributes to proneness to chills from artistic, poetic, and musical expressions. These results open up a promising path towards studying the human attitude towards art, via both state-of-the-art genomics and intergenerational models of transmission.
Hsp90 buffers behavioral variability by regulating Pdf transcription in clock neurons of Drosophila melanogaster.
Coculla A, Feldmann C, Ogueta M … +3 more , Mews S, Langrock R, Stanewsky R
PLoS Genet · 2026 Feb · PMID 41701796 · Full text
Circadian rhythms are prevalent on Earth and temporally organize behaviour and physiology of organisms to occur in species-specific 'temporal niches'. However, species differ in how strictly individuals are controlled by...
Circadian rhythms are prevalent on Earth and temporally organize behaviour and physiology of organisms to occur in species-specific 'temporal niches'. However, species differ in how strictly individuals are controlled by their circadian clock, suggesting that it may offer a selective advantage for an individual to extend its temporal niche under certain circumstances, for example during stressful environmental conditions. A potential mechanism controlling temporal niche adherence involves the evolutionary capacitor and chaperon protein HSP90, known to assist the proper folding of important signalling molecules. If HSP90 becomes rate limiting (e.g., under environmental stress) hidden genetic variation will be expressed, producing novel and potentially beneficial phenotypes for the individual. While this role of HSP90 is well established for morphological traits, we show here that it extends to regulation of temporal behavioural patterns. We show that within a small subset of clock neurons in the fly brain, HSP83, the fly homologue of HSP90, mitigates inter-individual behavioural variability. We provide evidence for the requirement of HSP83 for efficient transcription of the gene encoding the circadian neuropeptide Pigment Dispersing Factor (PDF), and for correct PDF accumulation in central clock neurons. Strikingly, Hsp83 mutants affect synchronized oscillations of the clock protein PERIOD (PER) in subsets of circadian clock neurons in the same way as flies without PDF, further supporting a role of Hsp83 in regulating Pdf. Our findings therefore provide a mechanistic explanation for HSP83 function in regulation of behavioural variability, and offer an explanation for how to restrict temporal niche extension to stressful environmental conditions.
Cholinergic signaling modulates intestinal pathophysiology in a Drosophila model of cystic fibrosis.
Lane EA, Petsakou A, Liu Y … +4 more , Chen W, Qadiri M, Hu Y, Perrimon N
PLoS Genet · 2026 Feb · PMID 41701793 · Full text
Cystic fibrosis (CF) is a monogenic genetic disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride/bicarbonate channel, which is expressed in certain epithelial cells. Curr...
Cystic fibrosis (CF) is a monogenic genetic disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride/bicarbonate channel, which is expressed in certain epithelial cells. Current therapies focus on restoring CFTR function, but many gut-related pathologies persist, highlighting the need for complementary treatments to improve the quality of life of people with CF. In this study, we use Drosophila melanogaster as a model to investigate the gut-specific effects of Cftr loss. We demonstrate that enterocyte specific knockdown of Cftr in flies recapitulates several CF pathologies, including reduced intestinal motility, nutrient malabsorption, and decreased energy stores. Using single-nuclei RNA sequencing (snRNA-seq), we identify significant transcriptional changes in the CF model gut, including the upregulation of acetylcholine esterase (Ace, human AChE), which leads to reduced cholinergic signaling. Cholinergic signaling has been shown to affect CFTR function but this is the first time CFTR loss of function has been shown to alter cholinergic signaling. Functional assays confirm that cholinergic sensitivity is diminished in CF guts. Furthermore, restoring cholinergic signaling via Ace knockdown rescues multiple CF-associated phenotypes. Additionally, we identify the transcription factor Fork head (Fkh), the Drosophila homolog of human FOXA1/FOXA2, which is known to be a positive regulator of Cftr transcription in the intestine, as a positive regulator of Ace expression in CF guts. This study establishes the Drosophila gut as a powerful model to investigate CF pathogenesis, genetic modifiers, and identifies Ace and fkh as genetic modifiers. This work also suggests that enhancing cholinergic signaling may represent a viable therapeutic strategy for gastrointestinal manifestations of CF.
Regulatory rewiring drives intraspecies competition in Bacillus subtilis.
Kalamara M, Bonsall A, Griffin J … +10 more , Carneiro J, Gierlinski M, Eigentler L, Stevenson D, Wood A, Porter M, Dorfmueller HC, MacPhee CE, Abbott JC, Stanley-Wall NR
PLoS Genet · 2026 Feb · PMID 41701782 · Full text
Intraspecies interactions shape microbial community structure and evolution, yet the mechanisms determining competitive outcomes among closely related strains remain unclear. The soil bacterium Bacillus subtilis is a mod...
Intraspecies interactions shape microbial community structure and evolution, yet the mechanisms determining competitive outcomes among closely related strains remain unclear. The soil bacterium Bacillus subtilis is a model for microbial social interactions, where quorum-sensing systems regulate cooperation and antagonism. Here, we take a multifaceted approach to dissect the role of quorum-sensing regulation in competitive fitness. Isolate NCIB 3610 carries a signal unresponsive RapP-PhrP module that alters quorum-sensing control and promotes faster growth. Modelling and mutant analysis demonstrate that the small differences in growth rate conferred by RapP-PhrP3610 are sufficient to drive competitive exclusion. The importance of quorum sensing control is further exemplified by experimental evolution of distinct wild isolates, which revealed recurrent mutations in the sensor kinase comP, which phenocopy complete comP or comA deletions and confer a growth-linked competitive advantage. Key quorum sensing mechanisms are abandoned even in structured microbial communities, where it might be expected that communal traits are favoured. Furthermore, a phylogenomic survey of 370 B. subtilis genomes identified disruptive comP mutations in ~16% of isolates. However, growth rate alone does not explain all interaction outcomes as even isogenic strains with equivalent doubling times differ in competitiveness. Transcriptomic profiling and validation experiments implicated a type VII secretion system toxin as an additional effector. These findings reveal that disruption of quorum-sensing pathways, whether naturally or through selection, provides a rapid route to competitive advantage, highlighting a fundamental trade-off between communal signalling and individual fitness in microbial populations.
Octopamine signaling from clock neurons plays dual roles in Drosophila long-term memory.
Kurata Y, Yoshii T, Sakai T
PLoS Genet · 2026 Feb · PMID 41701772 · Full text
Circadian clock genes are best known for regulating circadian rhythms, but they also play crucial roles in memory processes. This suggests that memory is modulated by neural networks containing clock neurons, although th...
Circadian clock genes are best known for regulating circadian rhythms, but they also play crucial roles in memory processes. This suggests that memory is modulated by neural networks containing clock neurons, although the underlying mechanisms remain unclear. In Drosophila melanogaster, approximately 240 clock neurons are grouped into at least eight distinct clusters. Among them, the dorsal-lateral neurons (LNds) are required for maintaining long-term memory (LTM). In contrast, the neuropeptide Pigment-dispersing factor (Pdf), expressed in both small and large ventral-lateral neurons (s-LNvs and l-LNvs, respectively), functions as a circadian output signal and is also essential for maintaining LTM. In addition, Pdf-expressing neurons (hereafter, Pdf neurons) release neurotransmitters other than Pdf, which are involved in LTM consolidation. However, the specific transmitters used by LNds and Pdf neurons in LTM processing have remained unknown. Here, we show that octopamine signaling from LNds is essential for LTM maintenance, whereas octopamine in Pdf neurons is essential for LTM consolidation. Temporally restricted knockdown of Tyramine β hydroxylase (Tbh), the gene encoding the enzyme required for octopamine synthesis, disrupted LTM maintenance when targeted in LNds, whereas it impaired LTM consolidation when targeted in Pdf neurons. Notably, Tbh knockdown in LNds or Pdf neurons had minimal effects on circadian behavioral rhythms or sleep. These findings reveal that octopamine released from specific subtypes of clock neurons independently regulates distinct phases of LTM in Drosophila.
Correction: Lack of ANKMY2 suppresses kidney cystogenesis in embryonic- and adult-onset polycystic kidney disease.
PLOS Genetics Staff
PLoS Genet · 2026 Feb · PMID 41701679 · Full text
[This corrects the article DOI: 10.1371/journal.pgen.1012008.].
[This corrects the article DOI: 10.1371/journal.pgen.1012008.].
PIKI-1, a class II PI 3-kinase, functions in endocytic trafficking.
Reimann GR, Edeen PT, Conquest S … +2 more , Grant BD, Fay DS
PLoS Genet · 2026 Feb · PMID 41686813 · Full text
Cellular membrane trafficking, including endocytosis and exocytosis, is a complex process coordinated by trafficking-associated proteins, cargo molecules, the cytoskeleton, and membrane lipids. The NIMA-related kinases N...
Cellular membrane trafficking, including endocytosis and exocytosis, is a complex process coordinated by trafficking-associated proteins, cargo molecules, the cytoskeleton, and membrane lipids. The NIMA-related kinases NEKL-2 (human NEK8/9) and NEKL-3 (human NEK6/7) are conserved regulators of membrane trafficking in Caenorhabditis elegans that are required for the completion of molting. Using a genetic approach, we isolated reduction-of-function mutations in piki-1 that suppress nekl-associated molting defects. piki-1 encodes the sole predicted C. elegans Class II PI 3-kinase (PI3K), a relatively understudied class of lipid modifiers that contribute to the production of PI 3-phosphate (PI(3)P) and PI 3,4-bisphosphate (PI(3,4)P2). Using genetically encoded lipid sensors, we found that PIKI-1 was responsible for the production of PI(3,4)P2 in the C. elegans epidermis but played only a minor role in contributing to PI(3)P levels. Consistent with this, both PI(3,4)P2 and PIKI-1 partially colocalized to early endosomes, and reduction of PIKI-1 affected the size and protein composition of early endosomal compartments marked by RAB-5, EEA-1, and SNX-1. Reduced PIKI-1 also led to increased tubulation of endosomal compartments associated with recycling or the degradation of cellular debris. In contrast to studies using mammalian cell culture, PIKI-1 was largely dispensable for clathrin-mediated endocytosis in the worm epidermis, a polarized epithelium. Notably, reduction of PIKI-1 function mitigated defects in early endosomes associated with the depletion of NEKL-2. We propose that reduction of PIKI-1 function may suppress nekl molting defects by partially restoring endocytic trafficking function within a subset of compartments, including the early endosome. We also show that inhibition of HIPR-1, an ortholog of the mammalian PI(3,4)P₂-binding proteins, HIP1 and HIPR1, suppresses nekl molting defects, consistent with a model that loss of PIKI-1 alters the binding of endocytic regulators in a manner that partially compensates for the loss of NEKL-2 activity.
Genetic dissection of signalling pathways that mediate iron-related tumor growth in a Drosophila model.
Jin L, Gao F, Li P … +2 more , Yu C, Xiao G
PLoS Genet · 2026 Feb · PMID 41686790 · Full text
Iron dyshomeostasis is associated with various cancers. Here we explore the underlying mechanisms through which iron promotes tumor growth and metastasis using a Drosophila cancer model. In this model, cells iin the eye-...
Iron dyshomeostasis is associated with various cancers. Here we explore the underlying mechanisms through which iron promotes tumor growth and metastasis using a Drosophila cancer model. In this model, cells iin the eye-antennal imaginal disc co-express oncogenic Raf gain-of-function and Scribbled loss-of-function mutants, leading to tumor formation. First, we show that dietary iron overload enhances tumor growth, invasiveness and mobility of cancer cells, whereas iron chelation suppresses these phenotypes. Consistently, RNA interference (RNAi)-mediated knockdown of dZIP13, a zinc transporter that transports iron into the secretory pathway, results in cytosolic iron accumulation and exacerbates the cancer-like phenotypes. Second, we show that the activity of a ten-eleven translocation DNA dioxygenase (TET), which enables DNA demethylation, correlates with cellular iron bioavailability, consistent with the known requirement of iron in the catalytic site of this enzyme. Third, we show that the TET enzyme transcriptionally regulates a histone methylase responsible for the H3K27me3 epigenetic mark. Fourth, we demonstrate that the iron-dependent DNA demethylation and subsequent histone trimethylation events activate the JAK/STAT signalling pathway, which promotes tumorigenesis, including the recruitment and proliferation of hemocytes to the malignant tissue. These findings reveal a novel tumor-suppressor function for dZIP13, while providing molecular mechanisms for iron-mediated tumor progression.
Serine/threonine protein kinase phosphorylation of DosR alters target gene transcription mechanics and regulates Mycobacterium tuberculosis response to nitric oxide stress.
Sontag NR, Ruiz Manzano A, Ecker AMV … +2 more , Galburt EA, Tan S
PLoS Genet · 2026 Feb · PMID 41678523 · Full text
Successful host colonization by bacterial pathogens requires appropriate response and adaptation to environmental signals encountered during infection, with two-component systems (TCSs) and serine/threonine protein kinas...
Successful host colonization by bacterial pathogens requires appropriate response and adaptation to environmental signals encountered during infection, with two-component systems (TCSs) and serine/threonine protein kinases (STPKs) being two important signal transduction mechanisms. Mycobacterium tuberculosis (Mtb) possesses similar numbers of STPKs (11) and TCSs (12), but if and how these two regulatory systems coordinate to enable Mtb adaptation in response to key environmental cues remains poorly understood. Here, we identify extensive interactions between STPKs and TCSs, with a subset of STPKs demonstrating interactions with multiple TCS response regulators. STPK phosphorylation of purified DosR, the response regulator of the key nitric oxide (NO)/hypoxia-responsive TCS DosRS(T), decreased its binding to target promoter DNA and its ability to activate steady-state gene transcription, in marked contrast with the opposite phenotypes observed with the activated, phospho-aspartic acid form of DosR. Strikingly, a ΔSTPK Mtb mutant exhibited increased DosR regulon transcription at lower NO levels than wild type Mtb, illustrating how STPK phosphorylation of a TCS RR may act to restrict and fine-tune conditions in which activation occurs. Together, our results support a functional relationship between STPKs and TCSs, and shed light on the mechanisms underpinning STPK-TCS interplay.
The rewiring of a terminal selector regulatory cascade generates convergent neuronal laterality.
Castro DL, Dimov IM, Mackie M … +3 more , Carstensen HR, Barsegyan MT, Hong RL
PLoS Genet · 2026 Feb · PMID 41671266 · Full text
Neuronal identity is established and maintained by "terminal-selector" transcription factors, yet how these networks evolve remains unclear. We examined the specification of the chemosensory ASE and thermosensory AFD neu...
Neuronal identity is established and maintained by "terminal-selector" transcription factors, yet how these networks evolve remains unclear. We examined the specification of the chemosensory ASE and thermosensory AFD neurons in the nematode Pristionchus pacificus, a species that expresses the terminal-selector, Ppa-CHE-1, in both sensory neurons. To determine if the ASE neurons exhibit left-right laterality, we used HCR-FISH and transgenic reporters to discover 8 ASE left-right-specific and 3 AFD-specific receptor-type guanylyl-cyclases. Late embryos exhibit a multipotential state in which AFD precursors transiently co-express all three types of ASEL, ASER and AFD markers. A forward genetic screen for defects in ASER asymmetry identified a Ppa-DIE-1 homolog, whereas targeted mutations revealed the maintenance of AFD neuronal identity requires another terminal-selector, Ppa-TTX-1, and CNG channels, Ppa-TAX-2/TAX-4. Mutations in the microRNA miR-8345 and pash-1 responsible for miRNA-processing convert ASEL to ASER fate while changes to other conserved regions in the 3' UTR of the cog-1 homolog reveal multiple sites that act as a toggle between left/right ASE versus AFD identities. Together, these results demonstrate that P. pacificus deploys a miRNA-mediated regulatory repertoire to generate three distinct neuronal fates through the Ppa-cog-1 3' UTR as a key regulatory nexus.
A machine learning classifier to identify and prioritise genes associated with murine cardiac development.
Kabir M, Hartill V, Farr Iii GH … +9 more , Shaikh Qureshi WM, Baross SL, Doig AJ, Talavera D, Waterfield MR, Keavney BD, Maves L, Johnson CA, Hentges KE
PLoS Genet · 2026 Feb · PMID 41666193 · Full text
Congenital heart disease (CHD) is a major cause of infant mortality and presents life-long challenges to individuals living with these conditions. Genetic causes are known for only a minority of types of CHD. Discovering...
Congenital heart disease (CHD) is a major cause of infant mortality and presents life-long challenges to individuals living with these conditions. Genetic causes are known for only a minority of types of CHD. Discovering further genetic causes is limited by challenges in prioritising candidate genes. We examined a wide range of features of mouse genes, including sequence characteristics, protein localisation and interaction data, developmental expression data and gene ontology annotations. Many features differ between genes needed for cardiac development and non-cardiac genes, suggesting that these two gene types can be distinguished by their attributes. We therefore developed a supervised machine learning (ML) method to identify Mus musculus genes with a high probability of being involved in cardiac development. These genes, when mutated, are candidates for causing human CHD. Our classifier showed a cross-validation accuracy of 81% in detecting cardiac and non-cardiac genes. From our classifier we generated predictions of the cardiac development association status for all protein-coding genes in the mouse genome. We also cross-referenced our predictions with datasets of known human CHD genes, determining which are orthologues of predicted mouse cardiac genes. Our predicted cardiac genes have a high overlap with human CHD genes. Thus, our predictions could inform the prioritisation of genes when evaluating CHD patient sequence data for genetic diagnosis. Knowledge of cardiac developmental genes may speed up reaching a genetic diagnosis for patients born with CHD.
Spatially distinct FRL and Ena dependent actin networks coordinate nuclear positioning in Drosophila nurse cells.
Gombos R, Farkas D, Vedelek B … +2 more , Szikora S, Mihály J
PLoS Genet · 2026 Feb · PMID 41662444 · Full text
Position of the nucleus is dynamically controlled to ensure a variety of cellular functions in a broad range of organisms form yeast to human. Nuclear positioning in Drosophila nurse cells is crucial during dumping when...
Position of the nucleus is dynamically controlled to ensure a variety of cellular functions in a broad range of organisms form yeast to human. Nuclear positioning in Drosophila nurse cells is crucial during dumping when cells transfer their entire cytoplasmic content into the oocyte. An important prerequisite of effective dumping is the formation of an array of actin cables which holds the nucleus in a central position, thereby allowing transmission of the cytoplasmic cargo. Here we report the identification of FRL, a formin type of actin assembly factor, as a novel determinant of cytoplasmic actin bundle formation. We found that FRL and the formerly described Ena protein display a differential requirement. Comparison of the frl and ena loss of function situations revealed that FRL is mainly required for creation of the cytoplasmic actin subpopulation at stage 10B, while Ena mostly promotes formation of a ring canal attached actin array, already present at stage 7 and persists till dumping. Upon the concurrent absence of FRL and Ena the nuclear positioning actin cables are completely missing, strongly suggesting that nuclear positioning in the nurse cells requires the coordinated action of two spatially distinct actin networks.
An essential gene screening identifies yeast Mot1 as a suppressor of R-loops and genome instability.
Soler-Oliva ME, Domínguez-Sierra RA, Gaillard H … +1 more , Aguilera A
PLoS Genet · 2026 Feb · PMID 41662397 · Full text
Transcription is essential for cellular function, but it can also lead to genetic instability, particularly through the formation of secondary structures such as R-loops, which consist of an RNA-DNA hybrid and a displace...
Transcription is essential for cellular function, but it can also lead to genetic instability, particularly through the formation of secondary structures such as R-loops, which consist of an RNA-DNA hybrid and a displaced DNA strand. Unscheduled R-loop accumulation is a major source of DNA damage and has been associated with several human diseases, including cancer. While multiple factors involved in RNA biogenesis, export, and chromatin remodeling play a role in preventing R-loop accumulation, the function of essential proteins in R-loop metabolism remains unexplored. Here, we performed a genetic screening in Saccharomyces cerevisiae using over 1200 temperature-sensitive mutants to identify novel proteins involved in the prevention of R-loop-associated genomic instability. Our results reveal that the SWI/SNF-like protein Mot1 plays a key role in preventing R-loop accumulation and R-loop-associated genome instability. Its role is particularly important during S phase, where Mot1 dysfunction leads to R-loop dependent replication impairment, presumably due to transcription-replication conflicts (TRCs). Epistatic relationships between mutations in MOT1 and the S-phase specific DNA-RNA helicase SEN1 further support the role of Mot1 in TRCs. The study highlights the importance of transcriptional regulators in maintaining genome stability by mitigating TRCs and regulating R-loop homeostasis.
High-throughput analyses of a reconstituted diversity-generating retroelement identify intrinsic and extrinsic determinants of diversification.
Unlu I, Smiley MK, Potapov V … +3 more , Renoux-Martin Y, Sun ZY, Lim HC
PLoS Genet · 2026 Feb · PMID 41642819 · Full text
Diversity-Generating Retroelements (DGRs) are specialized genetic systems typically harnessed in nature to evolve new molecular recognition. This mechanism, known as mutagenic retrohoming, relies on an error-prone revers...
Diversity-Generating Retroelements (DGRs) are specialized genetic systems typically harnessed in nature to evolve new molecular recognition. This mechanism, known as mutagenic retrohoming, relies on an error-prone reverse transcriptase (bRT) that introduces errors at template adenines, followed by the incorporation of the resulting mutagenized complementary DNA (cDNA) into a homologous target gene. Although widely distributed, DGRs are conspicuously absent from key bacterial models, limiting our understanding of their functionality in these hosts and their potential as engineering tools. Here, we demonstrate the 'plug-and-play' nature of the Bordetella phage BPP-1 DGR by successfully reconstituting the mutagenic retrohoming mechanism in Escherichia coli. Using high-throughput tools available in this tractable bacterium, we identified key regulatory factors that allowed us to enhance DGR efficiency over 1000-fold. Systematic analysis defines how sequence context governs bRT's fidelity, uncovering a distinct error profile for the AAC motifs prevalent in natural DGR templates. This intrinsic bias prioritizes the sampling of residues essential for antigen recognition, effectively focusing the evolutionary search within the most productive regions of sequence space. Furthermore, a transposon sequencing screen identified the single-stranded DNA exonuclease ExoI as an inhibitor of DGR activity. While removing ExoI enhanced activity by more than ten-fold, we found that its nuclease activity was dispensable for this inhibition, suggesting a non-catalytic mechanism. Finally, a genome-scale survey highlighted enhanced DGR efficiency at targets located near the replication origin and oriented outwardly from it. This bias is clearly linked to replication directionality, suggesting that certain aspects of DNA replication cycles promote mutagenic retrohoming. Collectively, our work reveals previously unappreciated mechanistic features of DGRs and establishes this reconstituted system as a powerful platform for targeted gene diversification and clarifying the molecular mechanism of mutagenic retrohoming.
Spatial microenvironments tune immune response dynamics in the Drosophila larval fat body.
Schlomann BH, Pai TW, Sandhu J … +3 more , Ferrer Imbert G, Graham TGW, Garcia HG
PLoS Genet · 2026 Feb · PMID 41632823 · Full text
Immune responses in tissues display complex spatial patterns of gene expression that are linked to disease outcomes. However, the processes that generate these patterns-including the relative roles of noisy gene expressi...
Immune responses in tissues display complex spatial patterns of gene expression that are linked to disease outcomes. However, the processes that generate these patterns-including the relative roles of noisy gene expression dynamics, microbial transport, and tissue anatomy-are poorly understood. As a tractable model of spatial immune responses, we investigated heterogeneous expression of antimicrobial peptides in the larval fly fat body, an organ functionally analogous to the liver. To quantify single-cell antimicrobial peptide expression dynamics in the fat body, we developed a protocol for light sheet fluorescence microscopy of whole, live larvae. Using this approach, we discovered that individual fat body cells express antimicrobial peptides at approximately constant rates following infection, but that the average rate varies along the anterior-posterior axis of the fat body, with rapid expression in the anterior and posterior lobes. Overexpression of immune signaling components and analysis of spatial transcriptomes revealed that these tissue microenvironments are predefined independently of infection, with the rate-limiting step of antimicrobial peptide induction downstream of peptidoglycan sensing. The locations of these microevironments correlate with heartbeat-dependent fluid flow in a manner resembling the strategic positioning of immune cells in the liver, gut, and lymph nodes of mammals. We speculate that this spatial compartmentalization helps the fat body efficiently perform its diverse metabolic, enzymatic, and immunological functions.
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