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PubMed2026

Swimming Upstream to Understand Congenital Anomalies of the Kidney and Urinary Tract: Zebrafish Models for Developmental Biology, Disease Mechanisms, and Functional Interpretation of Genetic Variation.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of pediatric chronic kidney disease (CKD) and comprise a heterogeneous group of developmental disorders with a substantial genetic contribution. Advances in next-generation sequencing have facilitated the identification of numerous candidate genes and rare variants associated with CAKUT. However, establishing causality and defining the biological functions of implicated genes remain major challenges. Functional validation is therefore essential to bridge the gap between gene discovery and mechanistic understanding, enabling the interpretation of genetic variation within the context of kidney development and disease. The zebrafish (Danio rerio) has emerged as a powerful in vivo model for studying renal development and interrogating the function of CAKUT-associated genes. Its utility stems from a high degree of genetic and developmental conservation with humans, conserved nephrogenic pathways, optical transparency during embryogenesis, and the relative ease of genetic manipulation. In this review, we provide an overview of zebrafish kidney development within the broader context of vertebrate nephrogenesis, highlighting the key genetic programs governing intermediate mesoderm specification, nephron segmentation, and pronephric morphogenesis. We then systematically examine CAKUT-associated genes that have been modeled in zebrafish, focusing on studies that have linked genetic perturbations to renal development and structural phenotypes. Finally, we discuss the strengths and limitations of zebrafish models for functional genomics and variant interpretation and consider their emerging role in bridging genetic discovery with mechanistic insights into CAKUT pathogenesis.

Animals↗

PubMed2026

Beyond Heritable PAH: Pulmonary Hypertension in Genetic Syndromes.

Pulmonary hypertension (PH) may complicate a broad range of genetic syndromes beyond the established spectrum of heritable pulmonary arterial hypertension. Although these conditions are individually rare, together they represent an emerging field at the crossroads of developmental biology, vascular medicine, and precision genomics. In many cases, PH may be the presenting feature or may remain unrecognized because it occurs within complex multisystem disorders involving congenital heart disease, developmental lung abnormalities, parenchymal lung disease, vascular malformations, or extra-pulmonary manifestations. Recent advances in human genetics have expanded the spectrum of genes and syndromes associated with PH, including disorders involving altered lung and vascular development, dysregulated hypoxia signaling, smooth muscle dysfunction, chromosomal abnormalities, and syndromic vasculopathies.In this review, we summarize the main genetic syndromes associated with PH and discuss their underlying mechanisms, clinical phenotypes, diagnostic clues, and therapeutic implications. We paid particular attention to conditions that illustrate the marked heterogeneity of syndromic PH such as FLNA-related disorders, neurofibromatosis type 1, Noonan syndrome, Down syndrome, Alagille syndrome, Cantú syndrome, Chuvash polycythaemia, cobalamin C deficiency, multisystemic smooth muscle dysfunction syndrome, alveolar capillary dysplasia with misalignment of pulmonary veins, and Moya Moya syndrome.

Journal Article↗

PubMed2026

RNA splicing and cardiovascular disease: a guide for cardiologists.

Alternative splicing (AS) is a fundamental RNA processing mechanism, which generates different RNA transcripts and consequently different protein isoforms from a single gene. This increases the diversity of proteins within an organism and can fine-tune biological processes. This review examines how cardiac-enriched RNA-binding proteins establish heart-specific splicing programs governing aspects of cardiac development, function, and disease. Developmentally, coordinated sarcomeric isoform switches underpin the foetal-to-adult transition and further isoform rewiring in ion channel and kinase genes determine electrophysiology and excitation-contraction coupling. AS contributes to the pathogenesis of several cardiomyopathies and emerging datasets suggest that pathological hypertrophy engages distinct splicing signatures compared with physiological hypertrophy. This review summarizes diagnostic and prognostic opportunities arising from bulk, long-read, and single-cell/nucleus transcriptomics, which resolve cell type-specific isoforms and disease-associated switches. Circulating RNA biomarkers (including splice ratios and circularRNAs) may signify myocardial remodelling and arrhythmic risk. Integrative approaches that link AS with proteomics and genomics improve variant interpretation, reveal previously unannotated protein isoforms, and enable tracking of disease progression and therapy response. Finally, an outline of therapeutic strategies to modulate AS in cardiovascular disease (CVD), including antisense oligonucleotides, small molecules, and genome-editing modalities (CRISPR, base, and prime editing), is provided. The major challenges that remain before splice-targeting therapeutics can be targeted to treat cardiovascular disease are highlighted. Lessons from neuromuscular indications establish clinical feasibility of splicing correction and motivate translation to cardiology. Together, mechanistic insight, biomarker development, and therapeutic innovation position RNA splicing as a tractable axis for precision cardiovascular medicine.

Humans↗

PubMed2026

TriosCompass: a snakemake workflow for integrated detection of SNVs, indels, STRs, and structural de novo variants in parent-child trios.

MOTIVATION: The accurate and sensitive identification of de novo variants, which are unique to an individual and not found in the parents' germlines, is critical for understanding the genetic basis of rare diseases, developmental disorders, and evolutionary processes. Existing de novo variant detection pipelines often lack the flexibility to handle multiple variant types, struggle with speed and reproducibility across computational environments, demand extensive manual configuration, or require bioinformatics expertise for downstream curation and analysis, limiting their scalability and usability for large genomic studies. Accordingly, there is a pressing need to better address these challenges. RESULTS: We introduce TriosCompass, an open-source Snakemake workflow that addresses these challenges by providing a modular, accelerated, and environmentally-configurable end-to-end solution for comprehensive de novo variant discovery. It integrates state-of-the-art tools into a reproducible framework, empowering researchers to discover novel genetic insights with greater efficiency and reliability. AVAILABILITY: TriosCompass is implemented as a Snakemake workflow and is freely available at https://github.com/NCI-CGR/TriosCompass_v2 or on Zenodo (10.5281/zenodo.17981062). SUPPLEMENTARY INFORMATION: Supplementary data is available on GitHub at https://github.com/NCI-CGR/TriosCompass_v2/tree/manuscript/report_dashboards. Supplementary methods on DeepTrio benchmark runs can be viewed at: https://github.com/NCI-CGR/TriosCompass_v2/blob/manuscript/TriosCompass_Supp_Methods_deeptrio_benchmark.md.

Software↗

PubMed2026

Expanding the clinical spectrum of ARV1-related disease beyond classical developmental and epileptic encephalopathy.

PURPOSE: Biallelic pathogenic variants in ARV1 are classically associated with developmental and epileptic encephalopathy-38 (DEE38), a severe infantile-onset disorder characterized by drug-resistant epilepsy, profound neurodevelopmental impairment, and early mortality. However, emerging evidence suggests broader phenotypic variability. We aimed to expand the clinical and molecular spectrum of ARV1-related disease through a retrospective case series and structured literature review. METHODS: We retrospectively identified five unrelated Saudi Arabian families with biallelic pathogenic or likely pathogenic ARV1 variants confirmed by whole-exome sequencing. Clinical, neurodevelopmental, neurophysiological, neuroimaging, and multisystem findings were reviewed. A structured literature review was performed to integrate previously reported cases. RESULTS: We identified marked clinical heterogeneity, including a novel ARV1 missense variant (c.214G>T; p.Asp72Tyr), which remains classified as a variant of uncertain significance according to ACMG/AMP criteria despite multiple computational predictions supporting a deleterious effect. Clinical severity ranged from severe developmental and epileptic encephalopathy with drug-resistant epilepsy and early mortality to milder static neurodevelopmental phenotypes with sustained seizure remission and long-term survival into adulthood. Families harboring the same homozygous frameshift variant exhibited markedly different clinical severity, supporting the absence of a strict genotype-phenotype correlation. Multisystem involvement included neurological, cardiac, skeletal, sensory, gastrointestinal, and genitourinary manifestations, and metabolic phenocopies contributed to diagnostic delays. CONCLUSION: Our findings demonstrate that ARV1-related disease represents a broad multisystem clinical spectrum, with classical DEE38 representing its most severe presentation rather than its sole manifestation. Recognition of milder phenotypes, prolonged seizure remission, and marked phenotypic variability has important implications for diagnosis, prognostic counseling, and multidisciplinary long-term surveillance. Early genomic testing should be considered in patients with early-onset epilepsy and multisystem involvement, particularly in consanguineous populations.

ARV1↗

PubMed2026

Genetic background influences developmental airway smooth muscle program and susceptibility to airway hyperresponsiveness in mice.

Airway structural remodeling and hyperresponsiveness (AHR), hallmarks of asthma, are influenced by genetic variations and adverse exposures. While intrauterine perturbations in lung development have been linked to adult pulmonary disease, the developmental origins of these abnormalities remain poorly understood. Here, we provide evidence of genetic background playing a key role in this process. Using A/J and C57BL/6J mice known for their distinct susceptibility to AHR, we show that A/J embryos selectively develop an aberrant airway smooth muscle (SM) program and AHR in adulthood when exposed transiently to a vitamin A/retinoic acid (RA)-disrupted intrauterine environment in vivo by maternal BMS493 administration. Single-nucleus multiomics identified a mesenchymal cell population overactivating TGF-β targets in response to BMS493 selectively in A/J lungs. These cells, localized to sites of airway SM initiation and p-SMAD2- and -3, exhibited robust BMS493-mediated upregulation of SMAD2/3 targets, including regulators of SM program Pdgfra and Tnc. Functional analyses in vivo and cultured lungs showed aberrant SM formation in areas of overactive TGF-β of BMS493-exposed lungs. These abnormalities were prevented by inhibiting TGF-β signaling in utero in RA-deficient embryos. These findings underscore how distinct genetic backgrounds respond to intrauterine perturbations that program airway structure and function, with potential lasting consequences in postnatal pulmonary function.

Animals↗

PubMed2026

Identification of mitochondrial energy metabolism-related candidate genes UQCR10 and NDUFA6 in pediatric tetralogy of fallot: an exploratory bioinformatics study.

BACKGROUND: Tetralogy of Fallot (TOF) is one of the most common cyanotic congenital heart diseases in infants and young children. Its molecular basis remains incompletely understood. This study aimed to identify mitochondrial energy metabolism-related candidate genes associated with pediatric TOF using public heart tissue transcriptomic datasets from the GEO database. METHODS: Datasets GSE146218 and GSE217772 were downloaded and merged, followed by batch-effect correction. Differential expression analysis was performed to identify differentially expressed genes (DEGs). Functional enrichment analysis, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network analysis were used to prioritize candidate genes. The Comparative Toxicogenomics Database (CTD) was used as an exploratory literature-based tool to summarize gene-disease associations. RESULTS: A total of 960 DEGs were identified. Functional enrichment analyses showed that these genes were mainly enriched in mitochondrial energy metabolism-related pathways, including oxidative phosphorylation and the mitochondrial respiratory chain. WGCNA and PPI network analyses further prioritized UQCR10 and NDUFA6 as candidate genes, and both genes showed increased expression in TOF heart tissue samples. CTD analysis suggested literature-based associations between these genes and cardiovascular or developmental disease-related terms. CONCLUSION: This exploratory bioinformatics study identified UQCR10 and NDUFA6 as mitochondrial energy metabolism-related candidate genes upregulated in pediatric TOF heart tissue. These findings suggest that mitochondrial respiratory chain-related transcriptional alterations may be involved in TOF-associated myocardial remodeling or stress responses. Further experimental and clinical validation is required to confirm their biological relevance.

Humans↗

PubMed2026

Decoding the mechanisms of cooperative DNA binding by the Paired-like homeodomain family.

The 36 Paired-like homeodomain transcription factors in humans are required for the development of many cell types, tissues, and organs as missense variants in 24 Paired-like genes have been associated with numerous diseases and developmental disorders. How these factors identify distinct genomic targets using highly similar DNA binding domains is not fully understood. Here, we focus on determining how the human Paired-like homeodomain factors gain DNA binding specificity by cooperatively binding palindromic sites spaced three base pairs apart (P3 site). Through structural, biochemical, and bioinformatic approaches, we define 11 rules that describe homeodomain residues that are critical, permissive, and inhibitory to cooperativity on the P3 site. Applying these rules, we successfully alter the cooperative behavior of Paired-like factors, identify residues that prevent the related Antennapedia class of homeodomains from binding cooperatively, and predict that thirty-eight disease-associated missense variants across ten Paired-like proteins alter cooperativity. Using quantitative DNA binding assays, we confirm eleven of twelve of these disease-associated variants impact cooperativity but not DNA binding affinity. These findings reveal the importance of cooperativity in defining DNA binding specificity and highlight how missense variants associated with as many as fifteen different diseases can selectively disrupt cooperative DNA binding.

Humans↗

PubMed2026

Genomic Characterization of Classic Adamantinoma, Osteofibrous Dysplasia, and Osteofibrous Dysplasia-like Adamantinoma.

Classic adamantinoma, osteofibrous dysplasia (OFD), and OFD-like adamantinoma are rare bone tumors arising primarily in the tibiae. Their distinction can be challenging; data on their molecular pathogenesis remain limited. We searched our pathology files in 2004-2024 for available cases and performed targeted next-generation sequencing along with whole-genome single-nucleotide polymorphism arrays and 3-dimensional genomics/Hi-C sequencing in selected cases. Our cohort included 3 classic adamantinomas (2 females and 1 male; age, 14-56 years), 5 OFDs (3 females and 2 males; age, 9-25 years), and 2 OFD-like adamantinomas (1 female and 1 male; age, 30-41 years). Of the 10 tumors, 9 arose from the tibiae; 1 classic adamantinoma originated from the radius. The 3 classic adamantinomas harbored multiple copy number gains involving chromosome 7, 8, 10, 12, and/or 19. Focal deletion of chromosome 17, intergenic rearrangement involving FGFR1, and NRAS p.G12D were each present in 1 classic adamantinoma. Of the 5 OFDs, KMT2A p.C2441F, KMT2D p.S1040P, PHOX2B p.G213D, and RIF1 deletion were each present in 1 case; no additional copy number/single-nucleotide variants were identified. Of the 2 OFD-like adamantinomas, one case with tumor clusters visible only on cytokeratin immunostain harbored no variants, whereas another case with tumor clusters visible on light microscopy and cytokeratin/p40 immunostains showed gains of chromosome 7, 8, 19, and 20. By Hi-C, 1 classic adamantinoma harbored an approximately 9 Mb tandem duplication on chromosome 12q, 1 OFD harbored a rearrangement with breakpoints near MECOM and HOOK3, and the OFD-like adamantinoma with tumor clusters visible only on cytokeratin immunostain harbored no structural variant. In conclusion, classic adamantinomas and OFD might be genetically distinct. Classic adamantinomas harbored multiple alterations, including chromosome/arm-level copy number gains, the detection of which could aid their distinction from OFDs. Using genomics as the benchmark, OFD-like adamantinomas might be better delineated by light microscopy or p40 than by cytokeratin immunohistochemistry. These data expanded our molecular understanding of these rare bone tumors.

Humans↗

PubMed2026

GlycoRNA complexed with heparan sulfate regulates VEGF-A signalling.

Heparan sulfate proteoglycans (HSPGs) have been recognized as key plasma membrane-tethered co-receptors for a broad range of growth factors and cytokines containing cationic heparan-binding domains1,2. However, how HSPGs mechanistically mediate signalling at the cell surface-particularly in the context of cell surface RNA-remain poorly understood. During developmental and disease processes, vascular endothelial growth factor (VEGF-A), a heparan sulfate-binding factor, regulates endothelial cell growth and angiogenesis3. The regulatory paradigm for endothelial cell-mediated selectively of VEGF-A binding and activity has largely been focused on understanding the selective sulfation of the anionic heparan sulfate chains4-8. Here we examine the organizational rules of a new class of anionic cell surface conjugates, glycoRNAs9,10, and cell surface RNA-binding proteins (csRBPs11,12). Leveraging genome-scale knockout screens, we discovered that heparan sulfate biosynthesis and specifically the 6-O-sulfated forms of heparan sulfate chains are critical for the assembly of clusters of glycoRNAs and csRBPs (cell surface ribonucleoproteins (csRNPs)). Mechanistically, we show that these clusters antagonize heparan sulfate-mediated activation of ERK signalling downstream of VEGF-A. We demonstrate that the heparan sulfate-binding domain of VEGF-A165 is responsible for binding RNA, and that disrupting this interaction enhances ERK signalling and impairs vascular development both in vitro and in vivo and is conserved across species. Our study thus uncovers a previously unrecognized regulatory axis by which csRNPs negatively modulate heparan sulfate-mediated signalling in the context of angiogenesis driven by VEGF-A.

Heparan Sulfate↗

PubMed2026

Losartan shows limited benefit in preclinical models of Geleophysic dysplasia.

Geleophysic dysplasia (GD) is a rare genetic disorder characterized by short stature, joint contractures, and cardiopulmonary complications, with early mortality, and linked to mutations in ADAMTSL2 (GD1), FBN1 (GD2), or LTBP3 (GD3) genes. These mutations are hypothesized to disrupt extracellular matrix (ECM) organization and enhance transforming growth factor beta (TGF-β) signaling. Losartan, an angiotensin II receptor blocker, has been proposed to mitigate TGF-β-mediated pathologies. In this study we tested the efficacy of losartan as a therapeutic drug for GD. We evaluated losartan's therapeutic potential using Adamtsl2 p.A165T mutant mice and patient-derived fibroblasts. Survival, growth, TGF-β signaling, and ECM protein expression were assessed. Losartan did not improve survival or growth in our mutant mice. Compared with control fibroblasts, patient-derived fibroblasts showed reduced basal TGF-β1 secretion. Consistent with this finding, transcriptomic analyses did not reveal activation of the TGF-β signaling pathway, and no differences in SMAD phosphorylation were observed between patient and control cells. Losartan treatment failed to modulate TGF-β signaling or ECM protein incorporation. These results suggest limited benefits of losartan in GD and challenge the notion of TGF-β dysregulation in GD pathogenesis, indicating a need for alternative targeted therapies.

Losartan↗

PubMed2011

Mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I.

Mutations in NF1 cause neurofibromatosis type I (NF1), a disorder characterized, among other clinical manifestations, by generalized and focal bony lesions. Dystrophic scoliosis and tibial pseudoarthrosis are the most severe skeletal manifestations for which treatment is not satisfactory, emphasizing the dearth of knowledge related to the biology of NF1 in bone cells. Using reporter mice, we report here that the mouse Col2α1-Cre promoter (collagen, type II, alpha 1) is active not only in chondrocytes but also in adult bone marrow osteoprogenitors giving rise to osteoblasts. Based on this finding, we crossed the Col2α1-Cre transgenic and Nf1(flox/flox) mice to determine whether loss of Nf1 in axial and appendicular osteochondroprogenitors recapitulates the skeletal abnormalities of NF1 patients. By microtomographic and X-rays studies, we show that Nf1(Col2)(-/-) mice display progressive scoliosis and kyphosis, tibial bowing and abnormalities in skull and anterior chest wall formation. These defects were accompanied by a low bone mass phenotype, high bone cortical porosity, osteoidosis, increased osteoclastogenesis and decreased osteoblast number, as quantified by histomorphometry and 3D-microtomography. Loss of Nf1 in osteochondroprogenitors also caused severe short stature and intervertebral disc defects. Blockade of the RAS/ERK activation characteristic of Nf1(-/-) osteoprogenitors by lovastatin during embryonic development could attenuate the increased cortical porosity observed in mutant pups. These data and the skeletal similarities between this mouse model and NF1 patients thus suggest that activation of the RAS/ERK pathway by Nf1 loss-of-function in osteochondroprogenitors is responsible for the vertebral and tibia lesions in NF1 patients, and that this molecular signature may represent a good therapeutic target.

Animals↗

PubMed2026

In Vivo Base Editing Partially Rescues Bone Dysplasia in a Mouse Model of Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most patients harbor a c.1824C>T/p.G608= variant, commonly described as G608G, in exon 11 of LMNA that leads to aberrant splicing and production of the toxic progerin protein. In addition to cardiovascular, dermal, and adipose tissue deterioration, HGPS mouse models also develop progressive bone dysplasia that occurs in patients. Here we characterize the efficacy of in vivo mutation correction with an adenine base editor (ABE) to rescue structural and functional defects in HGPS transgenic murine bone tissue. Treatment of double-copy transgenic osteoblast cultures with a lentiviral-delivered CRISPR-Cas9 ABE achieved nearly 40% gene correction in vitro, resulting in significant reduction of progerin transcripts and protein, in the absence of selective agents. Furthermore, gene correction improved progeroid osteoblasts' capacity to deposit and mineralize extracellular matrix compared to untreated cultures. In vivo, a single intravenous dose of AAV9-delivered ABE corrected the mutation, achieving ~14%, ~22%, ~10% and < 1% correction in bone by six months of age when administered at P3, P14, 1 and 4 months of age, respectively. Partially rescued bone structural and physical parameters were observed in P14-treated mice with concomitant normalization of gene transcriptional programs and intracellular signaling pathways involved in bone remodeling. This work demonstrates in vivo delivery of a locus-specific DNA base editor to bone tissue, delineates the timing of treatment required for maximum efficacy, and suggests that this system might be tailored for application to other monogenic bone disorders.

Animals↗

PubMed2025

Loss-of-Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype.

BACKGROUND: Mutations in cysteinyl-tRNA synthetase (CARS1) have been implicated in a multisystem disease including microcephaly, developmental delay, and brittle hair and nail phenotypes. METHODS: Here, we present a patient with hepatopathy, hypothyroidism, short stature, developmental delay, microcephaly, muscular hypotonia, brittle hair, and ataxia. The patient underwent exome sequencing to identify potentially pathogenic genetic variants. In addition, identified variants were assessed using yeast complementation assays to determine functional consequences. RESULTS: Exome sequencing determined that the patient is compound heterozygous for p.Arg341His and p.Arg370Trp CARS1. Yeast complementation assays showed that the p.Arg341His variant has a hypomorphic effect and that the p.Arg370Trp variant causes a complete loss-of-function effect. CONCLUSION: This study is the second report of pathogenic CARS1 variants and expands the allelic and phenotypic heterogeneity of CARS1-associated disease.

Humans↗

PubMed2026

Unusual Variants in NDUFAF6-Associated Mitochondrial Disease.

A 6-year-old female with global developmental delay, chronic kidney disease (stage III), and renal tubular dysfunction was evaluated in the National Institutes of Health Undiagnosed Diseases Program. Although exome sequencing did not yield a diagnosis, family genome sequencing revealed biallelic variants in NDUFAF6, i.e., a paternally inherited intronic variant (NM_152416.3:c.298-768T>C) and a maternally inherited 1.6 kb deletion (NC_000008.11:g.95044573_95046180del, spanning exon 5). NDUFAF6 plays an important role in mitochondrial complex I assembly by regulating ND1 biogenesis and facilitating the incorporation of NDUFS8. Variants in NDUFAF6 are associated with two OMIM disorders i.e., Fanconi renotubular syndrome 5 (OMIM #618913) and Mitochondrial complex I deficiency, nuclear type 17 (OMIM #618239). The associated phenotypes include proximal tubule dysfunction and degeneration of the central nervous system. The intronic single nucleotide variant in this case (sometimes referred to as the Acadian variant) has been reported to cause aberrant splicing. This case highlights the need to consider comprehensive sequencing methods, such as genome sequencing, to identify atypical variants in planning a comprehensive diagnostic strategy.

Mitochondrial disease↗

PubMed2026

Maternal obesity in rats results in male-specific increases in genome-wide DNA methylation in postnatal offspring liver.

Male-specific peripubertal DNA demethylation in the liver has been reported in mice. Here, we investigated whether it also occurs in rats, the influence of maternal obesity and whether DNA demethylation changes contribute to observed sex-specific effects of maternal obesity in offspring. Female rats were fed a high-fat, high-sugar 'cafeteria' (Caf) diet before mating with standard chow-fed males. The offspring liver methylome and transcriptome were examined. Body weight was higher in Caf-fed dams prior to mating, during gestation and at parturition. Male and female offspring from Caf-fed dams had lower birth weights but higher adult weights and adiposity than offspring from chow-fed dams. A comparison of DNA methylation in 3-week-old weaner males versus female siblings from chow-fed dams did not reveal the male-specific DNA demethylation that was previously reported in mice. However, strong maternal diet effects in male weaner offspring methylation were observed. A comparison of female weaners from chow- versus Caf-fed dams showed a range of differences, with 39% of differentially methylated regions (DMRs) having higher methylation in Caf offspring and 61% of DMRs having higher methylation in chow offspring. In stark contrast, 99% of maternal-diet-induced DMRs in male weaner offspring had higher methylation in offspring from Caf-fed dams. This suggests that maternal obesity induces widespread hypermethylation in the male offspring liver at weaning. However, a comparison with RNA sequencing data revealed limited transcriptional changes at this developmental stage or in adult offspring. While these data highlight how environmentally sensitive DNA methylation is in the male rodent perinatal period, these methylation changes may not be a major contributor to sex differences in developmentally programmed liver disease.

Animals↗

PubMed2026

Zebrafish as a versatile model in biomedical research, from disease modeling to regenerative medicine: a review.

Zebrafish are an effective animal model widely utilized in biomedical research. They are known for their rapid reproduction and substantial genetic similarity to humans. Their transparent embryos directly enable the visualization of developmental processes and disease progression. This makes zebrafish invaluable for studying a broad range of human diseases, including cancer, cardiovascular disorders, and neurodegenerative conditions. Compared with other vertebrate models, zebrafish offer several advantages, including ease of genome editing, cost-effective maintenance, and suitability for high-throughput drug screening. Recent advancements have expanded the use of zebrafish in disease modeling and regenerative medicine, providing deeper insights into the genetic and cellular mechanisms underlying human pathologies. Zebrafish provide a robust platform for evaluating the safety, efficacy, and regenerative potential of both natural and synthetic biomaterials, including hydroxyapatite, bioactive glass nanoparticles, and bioceramics. This capability facilitates the creation of artificial tissues that closely resemble native structures. Additionally, integrating artificial intelligence technologies has improved automated data analysis and phenotyping in zebrafish studies, enhancing both accuracy and throughput. This review highlights current applications of zebrafish in disease modeling, drug discovery, regenerative medicine, and biomaterial assessment, emphasizing their evolving role as a versatile preclinical platform supported by advanced genetic and computational tools.

Animals↗

PubMed2026

The emergence and diversification of the DUX gene family across placental mammals.

The DUX gene family encodes transcription factors with paired homeodomains. It has critical roles in embryogenesis and disease, including facioscapulohumeral muscular dystrophy (FSHD) and cancer. This study conducts a comparative analysis of the DUX gene family-DUXA, DUXB (including DUXBL), and DUXC (including DUX4 and Dux)-across placental mammals, highlighting their structural diversity within macrosatellite repeat contexts. Using long-read genomes, we explore gene distribution, array patterns, and phylogenetic relationships in various vertebrate species. Our analysis reveals that DUXA and DUXB are highly conserved, with intriguing variations such as intronless forms likely arising from ancestral retrotransposition events. While DUXBL is inconsistently retained across clades, its locus-which in non-placental mammals harbors the ancestral single-homeodomain sDUX gene-served as an evolutionary hub for diversification, giving rise to DUXA, DUXB and DUXC, as well as macrosatellite tandem array structures. Sequence conservation and syntenic analyses demonstrate array adaptability, exemplified by higher-order repeats in orangutans and disrupted patterns of concerted evolution in elephants. Furthermore, analysis of human pseudo-DUX4 arrays indicates their potential role in disease mechanisms, including as possible contributors to rare cases of FSHD, warranting further investigation. This study thus provides insights into DUX-family gene evolution, offering a foundation for future research into developmental roles and disease implications.

Animals↗