PLoS Genet. [JOURNAL]
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200 papers
MR2G: A novel framework for causal network inference using GWAS summary data.
Lin Z, Pan W, Xue H
PLoS Genet · 2026 May · PMID 42189912 · Full text
Inferring a causal network among multiple traits is essential for unraveling complex biological relationships and informing interventions. Mendelian randomization (MR) has emerged as a powerful tool for causal inference,...
Inferring a causal network among multiple traits is essential for unraveling complex biological relationships and informing interventions. Mendelian randomization (MR) has emerged as a powerful tool for causal inference, utilizing genetic variants as instrumental variables (IVs) to estimate causal effects. However, when the directions of causal relationships among traits are unknown, reconstructing the underlying causal network becomes challenging. In particular, the presence of cycles or feedback loops, which are common in biological systems, poses additional challenges for causal network inference, and remains largely under-studied with standard MR approaches and existing IV-based network inference methods. To address these issues, we introduce MR2G, a new statistical framework that enables robust inference of causal networks, including those with cycles, directly from GWAS summary statistics. MR2G is built on a formally defined recursive causal graph model that rigorously links direct causal effects to (univariable) MR estimands. It recovers a biologically interpretable causal network from pairwise MR effect estimates, while incorporating a network-informed IV screening strategy to reduce pleiotropic bias and improve robustness. Through realistic simulations, MR2G demonstrates superior accuracy and robustness in recovering complex causal structures, including those involving feedback loops. We apply MR2G to GWAS summary statistics for six complex diseases and nine cardiometabolic risk factors. MR2G not only recovers well-established causal pathways but also uncovers multiple feedback relationships, highlighting its utility in disentangling complex and biologically plausible causal networks from large-scale genetic data.
Pre-cuticle DPY-6 acts as a blueprint for aECM periodic organization in C. elegans.
Mazzoli S, Sonntag T, Cadena E … +4 more , Valotteau C, Birnbaum SK, Sundaram MV, Pujol N
PLoS Genet · 2026 May · PMID 42189886 · Full text
Apical extracellular matrices (aECMs) are essential for tissue integrity and function in multicellular organisms, but there is limited understanding of how such matrices are assembled and organized in the extracellular e...
Apical extracellular matrices (aECMs) are essential for tissue integrity and function in multicellular organisms, but there is limited understanding of how such matrices are assembled and organized in the extracellular environment. The Caenorhabditis elegans cuticle, a model aECM that undergoes morphogenesis during each of the worm's four larval molts, requires periodic circumferential furrows for structural integrity and immune regulation. Here, we show that furrow collagens must be cleaved from their N-terminal transmembrane domain for secretion and depend on the mucin-like pre-cuticle protein DPY-6 for their periodic assembly. While DPY-6 is dispensable for initial embryonic furrow formation, it acts as a mold during subsequent molts, ensuring pattern replication via its C-terminal cysteine cradle domain. These results reveal a central role for a transient matrix factor in organizing a complex periodically structured aECM.
ZBP1 Drives CD8+ T cell-mediated anti-tumor immunity in head and neck squamous cell carcinoma.
Min Y, Song G, Yang L … +6 more , He L, Xu S, Gao K, Liu Z, Peng X, Dai L
PLoS Genet · 2026 May · PMID 42189863 · Full text
Head and neck squamous cell carcinoma (HNSCC) frequently resists PD-1 blockade due to an immunologically "cold" tumor microenvironment (TME). Here, we identify Z-DNA binding protein 1 (ZBP1) as a key immunoregulator that...
Head and neck squamous cell carcinoma (HNSCC) frequently resists PD-1 blockade due to an immunologically "cold" tumor microenvironment (TME). Here, we identify Z-DNA binding protein 1 (ZBP1) as a key immunoregulator that reprograms immune-suppressive TMEs. Integrated TCGA/SangerBox analyses revealed ZBP1 as a hub gene strongly correlated with cytotoxic CD8+ T cells (r = 0.48, p < 0.0001) and M1 macrophages (r = 0.39, p < 0.0001). Multi-model validation in 92 HNSCC specimens revealed elevated ZBP1 expression versus normal tissues (p < 0.01), co-localized with infiltrating CD8+/CD4+ T cells and CD68+ macrophages through multiplex immunofluorescence. Clinically, high ZBP1 predicted improved survival (HR = 0.61 for overall survival; HR = 0.45 for disease specific survival; p < 0.0001) and early-stage presentation (p = 0.004). Mechanistically, ZBP1 overexpression in SCC-7/MOC2 models suppressed tumor growth while enhancing IFN-γ+ CD8+ T cell activation and reducing M2 polarization (CD206+: 16.91% vs 38.19% in ZBP1-high vs control, p < 0.001). Single-cell transcriptomics uncovered ZBP1-driven TME remodeling through chemokine signaling networks and expanded effector T cell compartments, validated by 1.49-fold increased CD8+ T cell infiltration via flow cytometry. Spatial analysis revealed ZBP1 overexpression amplified immune cell crosstalk (1.65-fold interaction increase, p < 0.001), upregulating CD8+ T cell chemotaxis (CXCR3/CCR5-CCL5 axis) and effector functions (p < 0.0001). Concurrently, it suppressed immunosuppressive pathways through metabolic reprogramming, establishing ZBP1 as a dual regulator synchronizing lymphocyte recruitment and myeloid suppression. Our integrative approach bridges computational biology with functional validation, demonstrating ZBP1's capacity to convert "cold" tumors into immunologically active niches. This work positions ZBP1 as both a stratification biomarker for checkpoint inhibitor response and a therapeutic target for TME reprogramming in HNSCC.
An intronic variant in Ferredoxin Reductase (FDXR) creates a cryptic exon in Quarter Horses with Equine Juvenile Spinocerebellar Ataxia.
Brown BN, Dahlgren AR, Ghosh S … +11 more , Durbin-Johnson B, Willis A, Olivas C, York D, Grahn R, Bellone RR, Cortopassi GA, Miller AD, Brown CT, Woolard K, Finno CJ
PLoS Genet · 2026 May · PMID 42160398 · Full text
Equine Juvenile Spinocerebellar Ataxia (EJSCA) is a novel autosomal recessive neurologic disease in Quarter Horses. Affected foals display a progressive proprioceptive ataxia by 1-5 weeks of age, leading to recumbency an...
Equine Juvenile Spinocerebellar Ataxia (EJSCA) is a novel autosomal recessive neurologic disease in Quarter Horses. Affected foals display a progressive proprioceptive ataxia by 1-5 weeks of age, leading to recumbency and necessitating euthanasia. Whole genome sequencing was performed on 7 EJSCA cases and unaffected horses that included 4 obligate carriers, 4 unaffected half or full-siblings, and 28 unrelated, unaffected control Quarter Horses. An 82 kb region of association was identified (EquCab3.0, chr11: 6963986-7045999), containing 9 candidate SNPs across four genes (FADS6, FDXR, GRIN2C and TMEM104). Decreased FDXR mRNA expression and a cryptic exon was identified in spinal cord tissue from EJSCA cases via RNA-sequencing. One of the 9 associated SNPs (FDXR-203 c.177 + 1778G > C) was the eighth base pair of this cryptic exon. Affected foals were all homozygous for the variant. Protein concentrations of FDXR were lower in EJSCA cases in spinal cord and liver compared to unaffected controls. The FDXR-203 c.177 + 1778G > C mutation represents the first non-coding neurological genetic variant in horses. Additionally, this is the first genetic cause of a degenerative axonopathy in the horse and a spontaneous disease model to study FDXR pathology in humans.
Comparative whole-genome analyses of articular chondrocytes and skin fibroblasts reveal distinct genome instability landscapes in mesenchymal cell types.
Sauty SM, Shine J, Bostan H … +5 more , Li JL, Mieczkowski PA, Loeser RF, Diekman BO, Gordenin DA
PLoS Genet · 2026 May · PMID 42160391 · Full text
DNA damage lesions can result in mutations and genome rearrangements that are associated with cellular aging and diseases. The landscape of somatic mutations in individual tissue and cell types are dictated by their uniq...
DNA damage lesions can result in mutations and genome rearrangements that are associated with cellular aging and diseases. The landscape of somatic mutations in individual tissue and cell types are dictated by their unique physiological states, cellular functions, mutagenic exposures, and efficiency of DNA repair. Articular chondrocytes and skin fibroblasts are two cell types of mesodermal origin with distinct exposure to internal and external sources of DNA damage. While somatic genome instability features of skin fibroblasts have been well detailed, knowledge about mechanisms underlying genome changes in chondrocytes is scarce. Here, we took a whole-genome sequencing approach to evaluate the load, sources, and patterns of genome changes in 18 primary human chondrocyte clones from donors with and without osteoarthritis (OA). Findings in chondrocyte clones largely agreed with a recent study of 100 single-cell sequenced chondrocytes. We compared genome changes in chondrocytes with clonally-expanded human skin fibroblasts sequenced in our previous studies. We demonstrated that skin fibroblasts show a higher burden of somatic mutations, with an increased rate of mutation accumulation per cell division. Motif-centered analyses of mutation catalogues identified only endogenous sources of mutations in chondrocytes, as opposed to skin fibroblasts which also showed a heavy burden of UV-induced mutations. Spontaneous deamination of meCpG and mutagenesis by exposure to small epoxides and SN2 electrophiles showed higher mutagenic activities in chondrocytes compared to skin fibroblasts. Chondrocytes showed ubiquitous prevalence of indels in homonucleotide runs of ≥5 bases, while skin fibroblasts showed high contributions of UV-associated deletions of ≥5 bp not in repeats. Structural variants in rearrangement hotspots colocalized with human common fragile sites in skin fibroblasts, but not in chondrocytes. Together, our study comprehensively recorded genome instability features in chondrocytes and highlighted the unique mutagenesis landscapes of two mesenchymal cell types.
Correction: Alanine-scanning mutagenesis library of MreB reveals distinct roles for regulating cell shape and viability.
Maharjan S, Sloan R, Lusk J … +3 more , Bevienguevarr R, Surber J, Morgenstein RM
PLoS Genet · 2026 May · PMID 42160290 · Full text
[This corrects the article DOI: 10.1371/journal.pgen.1012070.].
[This corrects the article DOI: 10.1371/journal.pgen.1012070.].
Why recombination hotspots?
Joseph J, Brazier T, Raynaud M … +5 more , Glémin S, Baudat F, de Massy B, Lartillot N, Duret L
PLoS Genet · 2026 May · PMID 42154786 · Full text
Meiotic recombination is the process by which DNA is exchanged between parental chromosomes during the production of gametes in eukaryotes. This phenomenon has important implications for fertility, genetic diversity and...
Meiotic recombination is the process by which DNA is exchanged between parental chromosomes during the production of gametes in eukaryotes. This phenomenon has important implications for fertility, genetic diversity and genome stability. Intriguingly, not all regions of the genome are equally susceptible to recombine during meiosis. Instead, in many eukaryotes, recombination events are concentrated in short genomic segments called recombination hotspots. Since the first discovery of recombination hotspots, several theories have emerged to explain their existence. In this review, we discuss the relevance of these theories in regards of recent advances in characterizing the diversity and determinants of fine-scale recombination landscapes. Finally, we outline new research avenues for elucidating the evolutionary origins of recombination hotspots.
Correction: Eliciting priors and relaxing the single causal variant assumption in colocalisation analyses.
Wallace C
PLoS Genet · 2026 May · PMID 42154678 · Full text
[This corrects the article DOI: 10.1371/journal.pgen.1008720.].
[This corrects the article DOI: 10.1371/journal.pgen.1008720.].
Cas9-expressing HC-04 hepatocytes facilitate CRISPR-based analysis of Plasmodium falciparum sporozoite-host interactions.
Verzier LH, Hesping E, Doerflinger M … +2 more , Herold MJ, Boddey JA
PLoS Genet · 2026 May · PMID 42149978 · Full text
Sporozoites of Plasmodium falciparum, the deadliest malaria parasite, are injected into the skin by infected mosquitoes and must reach the liver to initiate infection. There, they invade hepatocytes and develop into exoe...
Sporozoites of Plasmodium falciparum, the deadliest malaria parasite, are injected into the skin by infected mosquitoes and must reach the liver to initiate infection. There, they invade hepatocytes and develop into exoerythrocytic merozoites that eventually enter the bloodstream and invade erythrocytes, causing malaria. The sporozoite's journey requires cell traversal, where sporozoites transiently enter and exit host cells, lysing membranes to move deeper into tissue and evade immune cell destruction. After reaching the liver and traversing several hepatocytes, sporozoites productively invade a final hepatocyte to establish an exoerythrocytic form. The molecular mechanisms underlying traversal, invasion, and intracellular development remain incompletely understood, particularly with respect to host factors. To address this, we engineered human HC-04 hepatocytes, the only known cell line supporting P. falciparum liver-stage development, to express Cas9-mCherry, enabling CRISPR-based functional genomics studies. We validated Cas9 activity of HC-04.2B3 and demonstrated successful guide-RNA-directed gene disruption via non-homologous end joining. Optimized traversal and invasion assays led to a robust cytometric readout suitable for screening human genes involved in P. falciparum infection. Disruption of 10 human genes previously implicated in infection by bacterial and viral pathogens confirmed utility of this platform. This study provides the basis for genome-wide CRISPR screens to uncover hepatocyte biology and host determinants of infection.
Spatiotemporal characterization of single-stranded DNA Intermediates after UV Irradiation: I: Post-replication gaps formed during slow growth.
Sharma N, Cherry ME, Henry C … +5 more , Wood EA, Robinson A, van Oijen A, Ghodke H, Cox MM
PLoS Genet · 2026 May · PMID 42133618 · Full text
When E. coli cells are UV irradiated, replisome encounters with some DNA lesions lead to lesion skipping and formation of ssDNA gaps. These gaps are protected by SSB and repaired through the RecFOR recombinational DNA re...
When E. coli cells are UV irradiated, replisome encounters with some DNA lesions lead to lesion skipping and formation of ssDNA gaps. These gaps are protected by SSB and repaired through the RecFOR recombinational DNA repair pathway. However, many questions about this pathway remain unanswered. Here, we used a fluorescent SSB fusion that supports normal growth in the absence of WT SSB under most conditions to directly visualize the real-time formation and resolution of ssDNA intermediates in cells lacking factors (RecB, RecJ, RecF, and RecO), that facilitate recombinational DNA repair pathways under slow growth conditions. Upon DNA damage, SSB-bound features of various sizes increased within these cells. In WT cells, ssDNA gaps appeared and were resolved at a steady state level that persisted for hours. Formation of most ssDNA gaps was not dependent on RecB function. Large increases in ssDNA gaps were observed in cells lacking RecFORJ functions, particularly in the absence of RecO. These findings indicate that: (a) When hundreds of UV lesions are introduced into the genome, at least some lesions remain unaddressed by nucleotide excision repair (NER) for several hours under slow growth conditions. (b) Replisome encounters with DNA lesions rapidly generate ssDNA gaps. (c) A relatively small portion of the ssDNA foci appearing in WT cells may reflect breaks processed by the RecBCD system. (d) Most prominent SSB features reflect post-replication gaps repaired by RecFORJ. Lack of RecFORJ functions leads to accumulation of unresolved gaps over time. (e) RecF is not required for post-replication gap formation. Overall, the results provide direct visualization of complex UV-induced changes in DNA metabolism caused by replisome encounters with UV-generated pyrimidine dimers. Combined with a decades-long literature of related results and proposals, a unified view of how E. coli responds to UV irradiation can be put forward.
Spatiotemporal characterization of single-stranded DNA intermediates after UV irradiation: II. Rapid growth and effects of recA and recJ.
Ripandelli RAA, Wood EA, Robinson A … +2 more , van Oijen AM, Cox MM
PLoS Genet · 2026 May · PMID 42133577 · Full text
Irradiation of E. coli with UV light results in the formation of post-replication gaps and induction of the SOS response. Here, we investigate the dynamics of single strand gap formation and resolution in cells growing w...
Irradiation of E. coli with UV light results in the formation of post-replication gaps and induction of the SOS response. Here, we investigate the dynamics of single strand gap formation and resolution in cells growing with a 50 min doubling time within specially designed microfluidic chips, making observations on fluorescent gap markers in individual cells over the course of 8 hours. In cells proficient for gap repair, irradiation with UV at 5 J/m2 triggers an immediate increase in the number and intensity of gap markers. Cells lacking recF, recO, or recA cannot repair gaps via the canonical gap repair pathway and exhibit elevated gap numbers and intensities over many hours. Major conclusions include: (1) Post-replication gaps are a major feature of DNA metabolism after UV irradiation. (2) The long-lived, high-intensity foci observed in recF, recO, or recA mutants are completely dependent on the RecJ nuclease. In the absence of other RecFOR pathway functions, RecJ-mediated enlargement of many gaps continues unabated for extended periods. (3) In the absence of RecA or other RecFOR pathway functions, cells accumulate repair intermediates that are bound by large numbers of SSB molecules. (4) In the absence of RecJ, other pathways, perhaps involving TLS, displace SSB in gaps. Our results also confirm, using a different experimental setup and protocol, that: (a) UV-related repair activities, including nucleotide excision repair of at least some lesions, may continue for multiple cell generations after exposure; and (b) we again see no evidence that RecF facilitates lesion skipping. Overall patterns of gap formation and resolution under rapid growth conditions are consistent with a burst of post-replication gap formation following UV irradiation, postulated in the accompanying report to rapidly trigger the SOS response.
Design and interpretation of eQTL-GWAS colocalisation studies: Lessons from a large-scale evaluation.
Reales G, Pullin JM, Manipur I … +2 more , Vigorito E, Wallace C
PLoS Genet · 2026 May · PMID 42102166 · Full text
Colocalisation analysis integrates GWAS and molecular QTL datasets to identify candidate effector genes. Even with a wide range of molecular QTLs, 40% or more of GWAS loci remain unexplained, leaving a "colocalisation ga...
Colocalisation analysis integrates GWAS and molecular QTL datasets to identify candidate effector genes. Even with a wide range of molecular QTLs, 40% or more of GWAS loci remain unexplained, leaving a "colocalisation gap". We systematically characterised two large-scale eQTL colocalisation studies, to describe the determinants of this gap and ultimately inform the selection and design of eQTL studies to close the gap. We analyse over 1.3 million colocalisation tests from Open Targets Genetics (OTG) and perform and analyse colocalisations from 14 immune-mediated disease (IMD) GWAS and 12 diverse immune cell eQTL studies, selected to cover a range of cellular granularities and sample sizes. We find that 50% of GWAS peaks in OTG and 34% in IMDs colocalised and were more likely to colocalise if they were located nearer to genes and had a more common lead variant. Colocalisation was also more likely to occur in disease relevant tissues. The lowest granularity immune cell eQTL studies had the largest sample sizes, the greatest eQTL discovery and produced the largest number of colocalisations, particularly for lower-frequency variants. However, while higher resolution eQTL studies detected fewer eQTLs, each of those eQTLs was more likely to colocalise with a GWAS peak, emphasising the importance of cell specific eQTLs. Indeed, over 50% of colocalisations were found in only one cell type. Overall, our results suggest that a diverse set of cells in different contexts, and large, high granularity studies will be needed to identify remaining colocalisations. In addition, we observed that 47% of GWAS peaks colocalised with multiple genes in OTG and 37% in IMDs. Through simulations, sensitivity analyses, and integration of enhancer-promoter capture data we find that multiple colocalisations likely represent coregulation. While disentangling causality from horizontal pleiotropy will ultimately require experimental perturbation, triangulation using different sources of observational data is likely to be necessary for gene prioritisation.
Simulated sample splitting approach to address biases due to instrument selection and participant overlap in two-sample Mendelian Randomization studies.
Forde A, Hemani G, Ferguson J
PLoS Genet · 2026 May · PMID 42102131 · Full text
Mendelian randomization (MR) is a popular statistical technique that uses genetic variants to explore causal relationships in observational epidemiology. Summary-level MR, the most common form, relies on published GWAS s...
Mendelian randomization (MR) is a popular statistical technique that uses genetic variants to explore causal relationships in observational epidemiology. Summary-level MR, the most common form, relies on published GWAS summary statistics to estimate causal effects between exposures and outcomes. However, empirical analyses tend to ignore issues relating to Winner's Curse of instrument effects, weak instrument bias and sample overlap. Our simulations and empirical analyses using the UK Biobank indicate that such mechanisms can induce substantial bias in routine MR approaches. We propose MR Simulated Sample Splitting (MR-SimSS), a novel method that corrects this bias requiring no additional data beyond GWAS summary statistics for the exposure and outcome of interest. It operates by simulating statistically independent sets of summary statistics, analogous to what would be produced by splitting the individual-level data into independent subsets, which can then be plugged into existing two-sample MR methods. With sufficient instrument variants, MR-SimSS is robust to a range of sample overlap scenarios, providing a practical and modular solution to Winner's Curse and weak instrument bias.
Tumour-driven lipid accumulation in oenocytes reflects systemic lipid alterations.
Liu C, Golenkina S, Fahey N … +2 more , Kumar P, Cheng LY
PLoS Genet · 2026 May · PMID 42096463 · Full text
Cancer cachexia is a multifactorial syndrome characterized by systemic metabolic dysfunction, including liver steatosis. In this study, we examined the role of larval oenocytes - hepatocyte-like cells, in a Drosophila mo...
Cancer cachexia is a multifactorial syndrome characterized by systemic metabolic dysfunction, including liver steatosis. In this study, we examined the role of larval oenocytes - hepatocyte-like cells, in a Drosophila model of cancer cachexia. We found that oenocytes in tumour-bearing larvae accumulate lipid droplets in response to tumour-secreted signals, Gbb and ImpL2. This lipid accumulation reflects systemic changes in lipid metabolism, responding to lipid metabolism manipulations in either the fat body or the muscle. Disrupting lipid synthesis/breakdown (via FASN1 and Bmm), storage (via Lsd2), or trafficking (via apolipoproteins) in these tissues significantly modulated lipid droplet accumulation in oenocytes. Moreover, oenocyte-specific knockdown of FASN1 reduced their lipid content and non-autonomously affected lipid droplet size in the fat body, suggesting cross-regulatory interactions between these tissues. Cachectic oenocytes also exhibited altered signaling profiles, characterized by reduced PI3K signalling. Enhancing PI3K signalling through Akt overexpression restored oenocyte size and reduced lipid levels; however, these changes did not significantly improve muscle integrity. Together, our data suggests that dynamic exchange of lipids occur between the fat body, oenocytes and the muscle during cancer cachexia. While the fat body and muscle lipid pools are key regulators of muscle integrity, oenocytes - despite their metabolic responsiveness, do not appear to play an active role in preserving muscle function during cachexia.
Tissue-specific transfer learning improves functional variant and therapeutic target discoveries in breast and prostate cancer.
Li Q, Wang D, Zhang Z … +10 more , Perera D, Chen Z, Wen W, MacDonald ME, Cai W, Yan J, Shu XO, Zheng W, Guo X, Long Q
PLoS Genet · 2026 May · PMID 42090444 · Full text
DNA foundation models trained on large-scale genomic and epigenetic datasets have shown promise for regulatory variant interpretation, yet their application to tissue-specific contexts remain limited. Here, we present a...
DNA foundation models trained on large-scale genomic and epigenetic datasets have shown promise for regulatory variant interpretation, yet their application to tissue-specific contexts remain limited. Here, we present a transfer learning (TL) framework to adapt Enformer, a deep neural network trained on 5,313 multi-omics tracks, to breast and prostate cancer using 275 and 357 tissue-specific transcription factor (TF) ChIP-seq tracks, respectively. We computed tissue-specific cis-regulatory activity (tCRA) scores for millions of single-nucleotide variants (SNVs) in genome-wide association study (GWAS) datasets and prioritized high-impact SNV subsets (1M, 1.5M, and 2M). These TL-prioritized variants demonstrated consistently greater enrichment in tissue-specific enhancers, cancer GWAS risk variants, and ClinVar pathogenic variants compared to the original Enformer model. Transcriptome-wide association studies (TWAS) using TL-based SNVs identified more cancer-relevant genes, many of which exhibited functional essentiality (DepMap), therapeutic tractability (drug databases), and disease relevance (DisGeNET). Notably, TL models outperformed the base model in identifying genes enriched for drug targets and clinically relevant disease associations. Our results show that TL-derived tCRA scores enhance regulatory variant prioritization and improve susceptibility gene discovery in a tissue-specific manner. Our study provides a generalizable framework for tailoring foundation models to disease-relevant contexts, with implications for variant interpretation, therapeutic target discovery, and precision medicine.
Correction: The foraging gene coordinates brain and heart networks to modulate socially cued interval timing in Drosophila.
Miao H, Li W, Huang Y … +1 more , Kim WJ
PLoS Genet · 2026 May · PMID 42085427 · Full text
[This corrects the article DOI: 10.1371/journal.pgen.1011752.].
[This corrects the article DOI: 10.1371/journal.pgen.1011752.].
KAT6A is essential for developmental control gene expression in neural stem and progenitor cells.
Voss AK, Eccles S, Wichmann J … +8 more , Abeysekera W, Bergamasco MI, Garnham AL, Ranathunga N, Yang Y, Bowden R, Smyth GK, Thomas T
PLoS Genet · 2026 May · PMID 42081590 · Full text
Heterozygous variants in the KAT6A gene encoding the histone lysine acetyltransferase KAT6A (MOZ, MYST3) cause Arboleda-Tham syndrome, a cognitive impairment syndrome. Histone acetylation is generally associated with act...
Heterozygous variants in the KAT6A gene encoding the histone lysine acetyltransferase KAT6A (MOZ, MYST3) cause Arboleda-Tham syndrome, a cognitive impairment syndrome. Histone acetylation is generally associated with active gene transcription. Genetic deletion of both alleles of the Kat6a gene in mice causes developmental defects including anterior homeotic transformation, cleft palate, interrupted aortic arch and cardiac septal defects. Loss of KAT6A impairs expression of HOX, DLX and TBX genes, which are essential for body segment identity specification, palate, heart and aortic arch development. However, the effects of loss of KAT6A on chromatin modifications and gene expression in neural cells, which are relevant to normal brain development and function, is still poorly understood. In this study, we used an automated high-throughput chromatin profiling method and RNA sequencing in mouse neural system and progenitor cells to assess the effects of loss of one or two alleles of Kat6a on gene expression, histone acetylation and methylation. We also assessed occupancy by a trithorax group protein and RNA polymerase II. Our data suggests two modes of action for KAT6A: (1) acetylation of histone H3 on lysine 23 at promoters and enhancers and (2) recruitment of the trithorax group protein MLL1 (KMT2A) to promote the expression of developmental genes, including SOX and homeodomain genes. Together, these two functions appear to be required for normal gene expression in neural progenitors and essential for proliferation and neuronal differentiation.
A novel role of tRNA-derived fragments in porcine granulosa-oocyte cell communication and cuproptosis.
Shen L, Zhao X, Wu S … +11 more , Lei Y, Liang S, Wang S, Dai H, Wang Y, Chen L, Zhao Y, Gan M, Xiao S, Zhou G, Zhu L
PLoS Genet · 2026 Apr · PMID 42060579 · Full text
Copper is essential for reproductive function, yet its accumulation can lead to cytotoxicity and cuproptosis. However, the specific molecular mechanisms underlying granulosa cell cuproptosis and follicular atresia remain...
Copper is essential for reproductive function, yet its accumulation can lead to cytotoxicity and cuproptosis. However, the specific molecular mechanisms underlying granulosa cell cuproptosis and follicular atresia remain unclear. Particularly, the molecular pathway by which tRNA-derived fragments (tRFs), recognized as crucial epigenetic regulators, are involved in the regulation of granulosa cell cuproptosis requires further elucidation. In this study, we indicated that copper accumulation disrupted mitochondrial respiration and protein lipoylation, resulting in impaired mitochondrial TCA cycling and subsequent cellular metabolic imbalance. Furthermore, a direct correlation was identified between tRFs and copper homeostasis. Functional analysis demonstrated that tRF-Gly-M3, produced by angiopoietin (ANG) splicing, was significantly upregulated in granulosa cells cuproptosis, and impaired mitochondrial function to induce cuproptosis by silencing the expression of GLS mRNA. tRF-Gly-M3 in exosomes secreted by cuproptosis-induced granulosa cells was high expression, and these exosomes could be delivered into oocytes. tRF-Gly-M3 also impaired oocytes mitochondrial metabolic function, inhibited oocytes maturation, first polar body extrusion and parthenogenesis via silencing GLS mRNA. Overall, our findings indicated that tRFs from granulosa cells could be intercellularly delivered to oocytes, effectively regulating oocyte development.
INS-17 acts as a nutrient deprivation signal to mediate adult IIS-regulated associative behaviors in C. elegans.
Leptich EJ, Vijayakumar P, Pietryk EW … +3 more , Williams MI, Rajupalem R, Arey RN
PLoS Genet · 2026 Apr · PMID 42048395 · Full text
Insulin/Insulin-like growth factor 1 (IGF-1) signaling (IIS) is a pleiotropic signaling pathway that functions across tissues to coordinate phenotypic changes in response to nutrient status. Thus, the ubiquity of the IIS...
Insulin/Insulin-like growth factor 1 (IGF-1) signaling (IIS) is a pleiotropic signaling pathway that functions across tissues to coordinate phenotypic changes in response to nutrient status. Thus, the ubiquity of the IIS pathway hinders efforts to elucidate the mechanisms driving specific IIS-related phenotypes. Previous research in the nematode worm C. elegans has demonstrated that loss of function of the IIS transmembrane receptor (IR) ortholog, DAF-2, results in a doubled lifespan and enhanced learning and memory behaviors in young and aged animals. However, these findings are the result of reducing DAF-2 receptor function rather than modulating ligand-receptor interactions. In the current study, we aimed to dissect ligand-receptor interactions that may regulate associative behaviors apart from canonical IIS lifespan phenotypes in C. elegans. To this end, we performed targeted genetic screening of Insulin-like Peptides (ILPs) previously identified as DAF-2 antagonists to test their role in learning and memory phenotypes. We discovered that only a single uncharacterized ILP, INS-17, is required for learning and memory. We also demonstrate that INS-17 is sufficient to confer extended memory ability and can promote the maintenance of learning and memory with age. Additionally, we observe that INS-17 regulates associative behaviors independent of lifespan, uncoupling some IIS-mutant phenotypes. We find that regulation of the ins-17 genetic locus explains its unique requirement among ILPs for learning and memory behaviors. Finally, we found that INS-17 acts to signal a state of nutrient deprivation. This activity is required to properly process stimulus valence to promote advantageous behaviors. Our findings deepen the understanding of how IIS can regulate specific phenotypic outputs in response to changes in internal metabolic states.
A positive feedback loop between sensory and octopaminergic neurons underlies nociceptive plasticity in Drosophila larvae.
Boivin JC, Zhao YQ, Zhu J … +3 more , Dakin JT, Ning J, Ohyama T
PLoS Genet · 2026 Apr · PMID 42048383 · Full text
Adaptive modulation of nociceptive behaviour based on prior experience is essential for responding effectively to environmental threats. In Drosophila larvae, nociceptive escape behaviours are robust and stereotyped, yet...
Adaptive modulation of nociceptive behaviour based on prior experience is essential for responding effectively to environmental threats. In Drosophila larvae, nociceptive escape behaviours are robust and stereotyped, yet emerging evidence suggests this can be modulated by experience and internal state. Here, we demonstrate that repeated activation of nociceptive sensory neurons enhances both the likelihood and intensity of nocifensive rolling, reflecting a form of behavioural sensitization. This heightened responsiveness is accompanied by a sustained increase in activity within nociceptive sensory neurons, suggesting that plasticity arises, at least in part, within the sensory compartment. We identified the neuromodulator octopamine as a critical regulator of the sensitization: signalling through the octopamine receptor OAMB is required to sustain elevated nociceptive gain, and feedback from one of octopaminergic neurons class, the ventral unpaired median (VUM) neurons, amplifies sensory neuron output. Together, these findings reveal an experience-dependent positive feedback loop in the nociceptive system, where neuromodulatory circuits tune behavioural output.
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