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PubMed2025

The skeletal muscle of aged male mice exhibits sustained growth regulatory transcriptional profile following glucocorticoid exposure compared with young males.

Excess glucocorticoids induce skeletal muscle myopathy by changing gene expression. Advanced age augments glucocorticoid-mediated muscle phenotypes, yet the transcriptional responses underlying those augmented phenotypes are unclear. The purpose of this study was to define the glucocorticoid-responsive transcriptome in young and aged muscle following both acute and more prolonged glucocorticoid treatment. Young (4-mo-old) or aged (24-mo-old) male mice were administered either an acute injection of dexamethasone (DEX) or vehicle or daily DEX or vehicle injections for 7 days. Muscles were harvested 6.5 h after the final or only injection. The tibialis anterior (TA) was selected for RNA sequencing analysis as DEX treatment lowered TA mass specifically in aged males. In silico analyses identified enriched pathways and transcription factors predicted to regulate DEX-sensitive genes. Acute DEX altered similar numbers of genes in young (950) versus aged males (913), although aged males had greater magnitudes of fold change. After 7 days of DEX treatment, aged muscle exhibited more DEGs compared with acute exposure (1,196 vs. 913), whereas young muscle exhibited fewer DEGs than after acute exposure (599 vs. 950). In aged males, glucocorticoid-sensitive genes were consistently enriched for growth regulatory processes across both time points, a pattern that was not evident in young males. Despite those age-associated transcriptional differences, the transcription factors predicted to regulate the glucocorticoid-sensitive genes were similar in young and aged males. These data expand our understanding into how aging modifies the transcriptional response to excess glucocorticoids in skeletal muscle.NEW & NOTEWORTHY Glucocorticoids promote mass loss in certain muscles with advanced age but not at younger ages. In a muscle whose mass is lost in response to elevated glucocorticoids only in advanced age in males, we show that glucocorticoids initiate a unique and exaggerated transcriptional profile after both acute exposure to the hormone and after prolonged treatment that is consistent with muscle atrophy. These findings expand our understanding of the effect primary aging has on glucocorticoid-induced atrophy in males.

Animals↗

PubMed2025

Transcriptional profiling of Hutchinson-Gilford Progeria patients identifies primary target pathways of progerin.

Hutchinson Gilford Progeria Syndrome (HGPS) is an ultra-rare pediatric premature aging disorder. The disease is caused by a point mutation in the LMNA gene leading to the production of the dominant-negative progerin isoform of the nuclear envelope protein lamin A. Disease severity and progression amongst the population of ~140 known patients is variable. Most of the mechanistic insights into the disease have come from studies using cellular or mouse models of HGPS. To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, we have performed transcriptomic analysis of a comprehensive set of HGPS patients. We find misexpression of several cellular pathways across the patient population, particularly of multiple signaling pathways as well as the Unfolded Protein Response (UPR) and mesodermal cell fate specification. Variability amongst individual patients was limited, with misregulation of the major pathways observed in most patients. Comparing the transcriptome of patients with an inducible HGPS cell model, we distinguished immediate-early cellular response pathways from secondary adaptive pathways and identified mTORC1, the UPR, UV response, apoptosis and TNFα signaling via NF-κB as primary targets of the disease-causing progerin protein.

Hutchinson-Gilford Progeria Syndrome↗

PubMed2025

IGF1R deficiency mitigates acute lung injury by promoting anti-inflammatory transcriptional profiles.

BACKGROUND: Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and COVID-19 are characterized by hyperinflammation, commonly referred to as "cytokine storm". The insulin-like growth factor (IGF) pathway, particularly the type 1 receptor (IGF1R), plays a critical role in lung homeostasis and has been implicated in the pathogenesis of pulmonary inflammatory diseases. In mice, widespread Igf1r deficiency attenuates lung inflammation and alveolar damage in bleomycin (BLM)-induced ALI. METHODS: We analyzed single-cell RNA sequencing datasets from lung tissue of COVID-19 cases and control donors as well as mouse lungs to determine Igf1r and IGF family expression across pulmonary cell types. Furthermore, we conducted bulk RNA sequencing on lungs from Igf1r-deficient mice three days after BLM or saline instillation, followed by differential expression and functional enrichment analyses. Findings were further tested through protein detection, assessment of DNA damage and methylation in lung tissues, and functional assays using Igf1r-deficient primary mouse embryonic fibroblasts (MEFs). RESULTS: IGF1R was broadly expressed across multiple cell types in both human and mouse lungs under normal and pathological conditions. Other IGF family members showed cell-type-specific expression, which was modulated by lung injury. Transcriptomic profiling revealed differentially expressed genes between BLM-challenged and control mouse lungs, detecting biological processes and signaling pathways involved in ALI pathobiology. Igf1r deficiency in BLM-challenged mice reversed a large fraction of the transcriptional changes triggered by BLM, including "cytokine storm"-related gene expression. Functional enrichment analysis additionally revealed significant modulation of pathways related to DNA damage, metabolic reprogramming, mitochondrial homeostasis, and epigenetic regulation. In vitro, Igf1r-deficient MEFs exhibited decreased mitochondrial respiration and glycolysis, protection against BLM-induced nuclear damage and mitochondrial accumulation, and decreased histone H3 acetylation. Moreover, Igf1r-deficient mouse lungs displayed increased global DNA methylation following BLM challenge. CONCLUSIONS: IGF1R is a key modulator of the inflammatory and molecular response to ALI pathogenesis. IGF1R deficiency dampens the "cytokine storm", modifies transcriptional and epigenetic profiles and promotes protective cellular responses. These findings highlight IGF1R signaling as a potential therapeutic target in ARDS and related lung injuries.

Animals↗

PubMed2024

Single cell RNA sequencing provides novel cellular transcriptional profiles and underlying pathogenesis of presbycusis.

Age-related hearing loss (ARHL) or presbycusis is associated with irreversible progressive damage in the inner ear, where the sound is transduced into electrical signal; but the detailed mechanism remains unclear. Here, we sought to determine the potential molecular mechanism involved in the pathogeneses of ARHL with bioinformatics methods. A single-cell transcriptome sequencing study was performed on the cochlear samples from young and aged mice. Detection of identified cell type marker allowed us to screen 18 transcriptional clusters, including myeloid cells, epithelial cells, B cells, endothelial cells, fibroblasts, T cells, inner pillar cells, neurons, inner phalangeal cells, and red blood cells. Cell-cell communications were analyzed between young and aged cochlear tissue samples by using the latest integration algorithms Cellchat. A total of 56 differentially expressed genes were screened between the two groups. Functional enrichment analysis showed these genes were mainly involved in immune, oxidative stress, apoptosis, and metabolic processes. The expression levels of crucial genes in cochlear tissues were further verified by immunohistochemistry. Overall, this study provides new theoretical support for the development of clinical therapeutic drugs.

Animals↗

PubMed2026

Single-cell transcriptional profiling identifies the swimming crab Portunus trituberculatus in response to bacterial infection.

Crustaceans rely entirely on innate immunity, yet the cellular composition, functional specialization, and pathogen-induced remodeling of their immune system remain poorly resolved. Here, we generated a high-resolution single-cell transcriptomic atlas of hemocytes from the swimming crab Portunus trituberculatus following Vibrio parahaemolyticus infection using 10× Genomics scRNA-seq. Seven putatively distinct hemocyte clusters were identified, including granulocytes, semigranular hemocytes, prohemocytes, unresolved hemocytes, hyalinocyte-like hemocytes, biosynthetically active secretory hemocytes, and regulatory hemocytes. Although the overall cellular composition remained relatively stable after infection, hemocytes exhibited pronounced cluster-specific transcriptional reprogramming involving Toll/NF-κB signaling, antimicrobial peptide synthesis and metabolic rewiring. By integrating single-cell and bulk transcriptomes, we identified multiple anti-lipopolysaccharide factors (ALFs) as key secretory effectors and experimentally validated their antibacterial activities. FITC-based bacterial engulfment assays and RNA-seq of sorted phagocytes demonstrated that phagocytic capability was shared across multiple hemocyte clusters. Notably, the immunoglobulin superfamily receptor DSCAM displayed extensive alternative splicing and strong infection-induced activation in unresolved hemocytes. Immune-training experiments showed that prior bacterial exposure was associated with altered DSCAM expression and reduced early cumulative mortality upon secondary challenge, suggesting a memory-like immune phenotype. These findings provide a foundational framework for understanding crustacean immunity and advancing disease-resistant breeding in aquaculture.

Antimicrobial peptides↗

PubMed2024

Transcriptional profiles of Microcystis reveal gene expression shifts that promote bloom persistence in in situ mesocosms.

Harmful algal blooms caused by cyanobacteria threaten aquatic ecosystems, the economy, and human health. Previous work has tried to identify the mechanisms that allow blooms to form, focusing on the role of nutrients. However, little is known about how introduced nutrients influence gene expression in situ. To address this knowledge gap, we used in situ mesocosms initiated with water experiencing a Microcystis bloom. We added pulses of nutrients that are commonly associated with anthropogenic sources to the mesocosms for 72 hours and collected samples for metatranscriptomics to examine how the physiological function of Microcystis and bloom status changed. The addition of nitrogen (N) as urea, but not the addition of PO4, resulted in conspicuous bloom persistence for at least 9 days after the final introduction of nutrients. The addition of urea initially resulted in the upregulation of photosynthesis machinery, as well as phosphate, carbon, and N transport and metabolism. Once Microcystis presumably became N-replete, upregulation of amino acid metabolism, microcystin biosynthesis, and other processes associated with biomass generation occurred. These capacities coincided with the upregulation of toxin-antitoxin systems, CRISPR-cas genes, and transposases suggesting that phage defense and genome rearrangement are critical in bloom persistence. Overall, our results show the stepwise transcriptional response of a Microcystis bloom to the introduction of nutrients, specifically urea, as it is sustained in a natural setting. The transcriptomic shifts observed herein may serve as markers of the longevity of blooms while providing insight into why Microcystis blooms over other cyanobacteria.IMPORTANCEHarmful algal blooms represent a threat to human health and ecosystems. Understanding why blooms persist may help us develop warning indicators of bloom persistence and create novel mitigation strategies. Using mesocosm experiments initiated with water with an active bloom, we measured the stepwise transcription changes of the toxin-producing cyanobacterium Microcystis in response to the addition of nutrients that are important in causing blooms. We found that nitrogen (N), but not phosphorus, promoted bloom longevity. The initial introduction of N resulted in the upregulation of genes involved in photosynthesis and N import. At later times in the bloom, upregulation of genes involved in biomass generation, phage protection, genomic rearrangement, and toxin production was observed. Our results suggest that Microcystis first fulfills nutritional requirements before investing energy in pathways associated with growth and protection against competitors, which allowed bloom persistence more than a week after the final addition of nutrients.

Microcystis↗

PubMed2025

Ancestry and somatic profile predict acral melanoma origin and prognosis.

Acral melanoma, which is not ultraviolet (UV)-associated, is the most common type of melanoma in several low- and middle-income countries including Mexico. Latin American samples are significantly underrepresented in global cancer genomics studies, which directly affects patients in these regions as it is known that cancer risk and incidence may be influenced by ancestry and environmental exposures. To address this, we characterise the genome and transcriptome of 123 acral melanoma tumours from 92 Mexican patients, a population notable because of its genetic admixture. Compared with other studies of melanoma, we found fewer frequent mutations in classical driver genes such as BRAF, NRAS or NF1. While most patients had predominantly Amerindian genetic ancestry, those with higher European ancestry had increased frequency of BRAF mutations and a lower median number of structural variants. The tumours with activating BRAF mutations have a transcriptional profile more similar to cutaneous non-volar melanocytes, suggesting that acral melanomas in these patients may arise from a distinct cell of origin compared to other tumours arising in these locations. KIT mutations were found in a subset of these tumours, and quadruple wild-type samples (non BRAF/NRAS/NF1/KIT) differed from mutated samples in their structural genomic profile and overall and recurrence-free survival patterns. Transcriptional profiling defined three expression clusters; these characteristics were associated with recurrence-free and overall survival. We highlight potential novel low-frequency drivers, such as PTPRJ, NF2 and RDH5. Our study enhances knowledge of this understudied disease and underscores the importance of including samples from diverse ancestries in cancer genomics studies.

Journal Article↗

PubMed2025

Fecal microbiota transplantation promotes type 2 mucosal immune responses with colonic epithelium proliferation in patients with recurrent Clostridioides difficile.

BACKGROUNDFecal microbiota transplantation (FMT) is the most effective therapy for recurrent Clostridioides difficile infection (rCDI), yet its mechanism of action remains poorly understood.METHODSWe report the results of a clinical trial of patients undergoing FMT therapy for rCDI (n = 16), which analyzed colon biopsies, plasma, PBMCs, and stool at the time of FMT and 2-month follow-up. Plasma and colon biopsy samples were also collected from healthy controls for comparison with patients with rCDI. Microbiome composition, colonic gene expression, and immune changes were evaluated through high-throughput sequencing and immunoprofiling via flow cytometry.RESULTSNo patients experienced recurrence at follow-up. FMT significantly altered the intestinal microbiome but had no significant impact on the systemic immune system. In contrast, FMT promoted broad changes in colonic transcriptional profiles compared with both pre-FMT and healthy control biopsies, inhibiting genes associated with proinflammatory signaling and upregulating type 2 immunity and proliferative pathways (Myc and mTORC1). FMT increased expression of IL-33 and the type 2 immune EGFR family ligand amphiregulin, potentially explaining upregulation of Myc and mTORC1 pathways. Spatial transcriptomics demonstrated that these changes were localized to the colonic epithelium. Comparison of transcriptional profiles with available single-cell gene sets determined that post-FMT biopsies were enriched in signatures associated with proliferative cell types while repressing signatures of differentiated colonocytes.CONCLUSIONWe conclude that FMT promotes proliferation of the colonic epithelium in patients with rCDI, which may drive regeneration and protect against subsequent CDI.TRIAL REGISTRATIONClinicaltrials.gov NCT02797288.FUNDINGThis work was funded by grants from the NIH.

Adult↗

PubMed2026

SpxA1 and SpxA2 function as a stoichiometry-dependent regulatory rheostat governing virulence gene expression in group A Streptococcus.

UNLABELLED: Group A Streptococcus (GAS) is a human-restricted pathogen whose global incidence has surged in the post-COVID era. The ability of GAS to shift from a colonizing to invasive phenotype depends on coordinated virulence gene regulation in response to host-derived signals. However, the mechanisms by which individual stress-sensing systems interact to reshape the virulence gene regulatory landscape remain incompletely understood. Here, we define the regulatory programs of two conserved transcriptional regulator paralogs, SpxA1 and SpxA2, using an integrated multi-omic approach combining RNA-seq, data-independent acquisition proteomics, NanoString-based transcriptional profiling across multiple host-relevant stress conditions, and chromatin immunoprecipitation with exonuclease treatment (ChIP-exo). RNA-seq revealed functionally distinct regulons with SpxA1 governing oxidative stress defense and SpxA2 coordinating virulence-associated gene expression linked to the CovRS two-component regulatory system. Proteomic analysis established SpxA2 as a ClpXP protease substrate in GAS and identified reciprocal paralog accumulation upon loss of either SpxA1 or SpxA2, consistent with compensatory transcriptional upregulation. NanoString profiling under bacitracin and human neutrophil peptide-1 challenge identified four gene modules with distinct stoichiometry-dependent and condition-dependent regulatory logic, revealing that the SpxA1/SpxA2 ratio rather than the activity of either paralog alone determines which transcriptional programs are engaged. ChIP-exo demonstrated that SpxA2 directly modulates CovR-DNA binding occupancy in a CovR-binding motif-dependent manner, simultaneously antagonizing CovR dimer binding at an extended (25 bp) CovR motif and facilitating CovR monomer binding at the canonical ATTARA motif. These findings establish the LiaFSR-SpxA2-CovRS axis as a cross-regulatory circuit through which GAS cell envelope stress sensing is directly transduced into coordinated virulence gene regulatory changes. IMPORTANCE: Group A Streptococcus (GAS) causes millions of infections annually, including a recent global surge in invasive disease. To survive in the human host, GAS must rapidly reprogram virulence gene expression in response to host-derived stresses. This study characterizes two conserved transcriptional regulators, SpxA1 and SpxA2, that govern this response through interaction with RNA polymerase to indirectly influence the DNA-binding activity of downstream transcription factors. We show that SpxA2, activated by a cell envelope stress-sensing system responding to human antimicrobial peptides, reshapes the binding of the master virulence regulator CovR in a promoter-specific manner, coupling cell envelope stress sensing to virulence gene regulation. The stoichiometric balance between SpxA1 and SpxA2 functions as a regulatory rheostat calibrating overall virulence gene regulatory tone, providing a framework for understanding how RNA polymerase-interacting regulators coordinate stress responses and virulence gene control across Gram-positive bacterial pathogens.

Streptococcus pyogenes↗

PubMed2024

Targeting the transcription factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C.

An understanding of the enzymatic and scaffolding functions of epigenetic modifiers is important for the development of epigenetic therapies for cancer. The H3K4me2/3 histone demethylase KDM5C has been shown to regulate transcription. The diverse roles of KDM5C are likely determined by its interacting partners, which are still largely unknown. In this study, we screen for KDM5C-binding proteins and show that YY1 interacts with KDM5C. A synergistic antitumor effect is exerted when both KDM5C and YY1 are depleted, and targeting YY1 appears to be a vulnerability in KDM5C-deficient cancer cells. Mechanistically, KDM5C promotes global YY1 chromatin recruitment, especially at promoters. Moreover, an intact KDM5C JmjC domain but not KDM5C histone demethylase activity is required for KDM5C-mediated YY1 chromatin binding. Transcriptional profiling reveals that dual inhibition of KDM5C and YY1 increases transcriptional repression of cell cycle- and apoptosis-related genes. In summary, our work demonstrates a synthetic lethal interaction between YY1 and KDM5C and suggests combination therapies for cancer treatments.

YY1 Transcription Factor↗

PubMed2026

Disentangling the cellular composition of FLCN-mutated tumors in Birt-Hogg-Dubé Syndrome by spatial transcriptomics.

Birt-Hogg-Dubé (BHD) syndrome is a hereditary cancer predisposition syndrome caused by pathogenic variants in the folliculin (FLCN) gene and is associated with an increased risk of multifocal renal tumors. FLCN-mutated tumors (FMTs) often exhibit morphological heterogeneity with mixed morphological features resembling renal oncocytoma (RO) and chromophobe renal cell carcinoma (chRCC), yet the molecular basis underlying the heterogeneous morphologic features and the morphologic-genomic correlations remain poorly defined. In our prior work, we identified mutually exclusive expressions of L1 cell adhesion molecule (L1CAM) and forkhead box I1 tboxI1 (FOXI1) labeling the two morphologically distinct cellular populations in BHD-associated FMTs, leading to the hypothesis that these two tumor compartments may have distinct molecular features and may reflect different nephron epithelial differentiation states. In this follow-up study, we tested this hypothesis using L1CAM and FOXI1 as morphology-guided markers for spatial transcriptomic profiling of the distinct tumor compartments in FMTs with the NanoString GeoMX Digital Spatial Profiler (DSP). Six FMTs from three patients with BHD and three normal kidney tissues were analyzed. L1CAM+ and FOXI1+ area of interest (AOI) were collected from tumor areas with various tumor compositions, including L1CAM+ dominant, FOXI1+ dominant, and mixed tumor areas. Spatial transcriptomic analysis identified distinct gene expression signatures in L1CAM+ and FOXI1+ FMT compartments independent of the local tumor compositions. FOXI1+ tumor cells showed robust enrichment for intercalated cells (IC)-associated gene signatures. In contrast, L1CAM+ tumor cells exhibited a heterogeneous transcriptional profile, with partial overlap across a spectrum of renal tubular epithelial cell types rather than a definitive principal cell-like identity. Despite this compartment-specific differences, both compartments share expression of a panel of tumor signature genes, including glycoprotein nmb (GPNMB) gene, and a core of cancer related biological functions and signaling pathways. Together, these findings refined the prior dichotomous model of BHD-associated renal tumors and support a model in which L1CAM+ and FOXI1+ tumor compartments represent divergent evolutionary or differentiation states with a common FLCN-mutant neoplastic transcriptional program. This spatial transcriptomic profiling provides molecular evidence for the morphological heterogeneity of FMTs and insights on the tumor biology of BHD-associated FMTs.

Birt-Hogg-Dubé↗

PubMed2026

Post-Hoc Long-Read Sequencing Links Leukemic Mutation Status to Single-Cell Transcriptomes.

Single-cell RNA-sequencing-based characterization of cells that belong to the neoplastic clone is a major challenge in hematologic neoplasms, where malignant and normal cells coexist. Confident molecular profiling requires simultaneous analysis of gene expression and genetic mutations in individual cells, an ability that is not supported by the standard 10X Genomics workflow. Here, we systematically evaluated the potential and limitations of repurposing amplified cDNA generated during the 10X Genomics 3' workflow for post hoc genotyping of individual cells. We first established a mixed leukemic cell line system comprising one cell line with KIT point mutations and another with the BCR::ABL1 fusion gene. Targeted long-read PacBio sequencing enabled post hoc assignment of mutation data to transcriptionally profiled cells, but recovery differed between targets. Consistent with ambient RNA in microfluidics-based single-cell workflows, mutation-associated transcripts were detected in cells not expected to carry the corresponding mutations, illustrating how transcript recovery complicates cell-level genotype assignment. Target-specific thresholds mitigated this source of misclassification. In primary chronic myeloid leukemia samples, the post hoc approach detected BCR::ABL1-positive cells at diagnosis, but not during imatinib treatment. Together, we present a framework for adding mutation status to cells already profiled using the 10X Genomics workflow and highlight broader considerations for transcript-based single-cell genotyping.

BCR::ABL1↗

PubMed2026

Hope is linked with more favorable tumor molecular signatures in serous ovarian cancer.

INTRODUCTION: Hope has been associated with improved quality of life and lower mortality in cancer, but the underlying biological mechanisms are poorly characterized. We previously reported that hope was associated with less inflammation and more normalized diurnal cortisol pre-treatment among women with ovarian cancer. We also reported associations of socio-environmental factors with pro-metastatic processes. Here, we used genome-wide transcriptional profiling to quantify associations between hope and tumor molecular signatures reflecting invasiveness, inflammation, and cellular immunity. METHOD: Participants were 74 women with serous ovarian cancer who provided demographic information and completed surveys pre-surgery. Hope was assessed using a face-valid item from the Center for Epidemiological Studies Depression Scale (CES-D). Depression was assessed using the full CES-D without the hope item. Illumina HT12 microarrays were used to assay tumor RNA, and associations between hope and tumor gene expression were quantified, adjusting for depression, age, BMI, grade, and stage. RESULTS: Adjusting for covariates, hope was associated with multiple favorable differences in RNA expression, including lower levels of mesenchymal differentiation (p = 0.008) and pro-inflammatory gene regulation (NF-κB: p < 0.001; IRF1: p = 0.024; STAT: p = 0.018), elevated epithelial differentiation (p = 0.011), and elevated activity of the IRF7 transcription factor which promotes cellular immunity (p = 0.016). CONCLUSIONS: These data suggest that hope is associated with an ovarian tumor gene expression profile characterized by reduced epithelial-mesenchymal transition (EMT) and inflammatory activity, and increased activity of a transcription factor promoting cellular immunity. These findings highlight potential biological implications of a resilience factor such as hope, but need replication with more robust assessments of hope.

Epithelial mesenchymal transition↗

PubMed2025

Modeling early gastrulation in human blastoids with DNA methylation patterns of natural blastocysts.

Blastoids are a promising model for studying early human embryogenesis, but current models have limitations in post-implantation development and lack comprehensive epigenetic assessments, especially regarding genomic imprinting. These issues can lead to failures in accurately modeling early embryonic development. In this study, we developed a high-fidelity blastoid model using 4 chemicals + leukemia inhibitory factor (LIF) (4CL) naive human pluripotent stem cells (hPSCs) (4CL blastoids). 4CL blastoids closely resemble human blastocysts in morphology and transcriptional profiles, exhibiting similar DNA methylation and gene imprinting patterns. By extending the 3D culture to 14 days, these blastoids mimic early gastrulation, demonstrating the specification and migration of cells. They also show the transcriptional signature of hemogenic angioblast (HAB) cells at Carnegie stage 6 (CS6). This model bridges pre- and post-implantation stages, offering valuable insights into early tissue formation and human development.

Humans↗

PubMed2026

Insights into the regulatory roles of LIKE-HETEROCHROMATIN PROTEIN 1 and its targeting to different nuclear compartments modulated by NLS and the conserved domains in the moss Physcomitrium patens.

LIKE-HETEROCHROMATIN PROTEIN 1 (LHP1) is a polycomb group protein that exists in shared multiprotein complexes that harbor core PRC1 and PRC2 proteins. We previously characterized LHP1 in the moss Physcomitrium patens and showed that its function is closely linked with regulation of RNA metabolic processes and the protein is distributed in the nucleoplasm, subnuclear foci, and the nucleolus. To gain mechanistic insight into PpLHP1-mediated gene regulation, in the present study genome-wide changes in transcript profiles of genes affected by loss-of-PpLHP1 function were studied using pplhp1 mutants. RNA-seq analysis reveals a key role for PpLHP1 in regulating energy metabolic processes, ribosome-related pathways, stress signaling/responsive pathways, DNA transcription, etc. ChIP using H3K27me3 coupled with qRT-PCR shows that PpLHP1 suppresses transcription at 5S rRNA promoters and the untimely activation of genes regulating developmental transition by PRC2-dependent and independent mechanisms. To study how PpLHP1 finds its targets in different nuclear compartments and the roles of the multiple NLSs and the conserved domains in guiding the protein, FRAP and deletion studies were performed. These show that PpLHP1 is a mobile protein that diffuses freely in the nucleoplasmic space showing different retention times in the nucleolus, nucleoplasm, and the subnuclear foci indicating its differential affinity for targets at these sites. Expression of PpLHP1 fragments in protonema cells and its subsequent visualization under confocal microscope shows that localization of PpLHP1 to different subnuclear compartments is guided by the monopartite NLS2, CD, and CSD that also play a key role in promoting subnuclear foci formation in the nucleoplasm.

Bryopsida↗

PubMed2025

RUNX1A isoform is overexpressed in acute myeloid leukemia and is associated with FLT3 internal tandem duplications.

RUNX1A is the shortest and least expressed of the RUNX1 three main isoforms (A, B, C); despite this, the leukemogenic role of its overexpression has been clearly described. Several studies have shown RUNX1A involvement in different blood cancers and pilot observations in acute leukemia have been reported. In this context, we evaluated RUNX1 isoforms expression in a cohort of acute myeloid leukemia (AML) patients, finding overexpression of RUNX1A and RUNX1B, with higher median levels in thrombocytopenic cases. No difference was observed for RUNX1C. RUNX1A overexpression is higher in more immature AML phenotypes. According to the mutational profile, FLT3 internal tandem duplication (ITD) positive cases have the highest RUNX1A levels and the presence of FLT3-ITD was the only molecular variable able to influence RUNX1A expression. RUNX1A overexpression is disease-related, associated with a specific transcriptional profile, and reappears at relapse, with no clear kinetics except in FLT3-ITD cases. Overall, we demonstrate RUNX1A overexpression in AML and its association with the FLT3-ITD molecular subtype. Our data shed light on the dark side of RUNX1 deregulation, paving the way for further investigations.

Humans↗

PubMed2026

Spatially guided in vivo single-cell functional genomics of postnatal heart.

Understanding how spatial organization and cell-cell interactions shape gene regulatory programs is central to decoding tissue development and function. The transition at birth, marked by increased circulatory demands and rapid tissue growth, requires precise spatiotemporal coordination of cardiac maturation. In this study, we generated a high-resolution spatial and temporal atlas of the postnatal mouse heart by integrating single-nucleus RNA sequencing with image-based spatial transcriptomics. This framework revealed dynamic cellular interactions, niche-specific signaling and transcriptional programs guiding cardiomyocyte maturation. To functionally test prioritized regulators in vivo and at scale, we developed PIP-seq (probe-based indel-detectable Perturb-seq), a high-throughput platform that detects single guide RNA identity, infers gene editing and profiles transcription from fixed nuclei. Applying PIP-seq to the developing postnatal heart, we identified 21 previously uncharacterized regulators of cardiomyocyte maturation, including genes essential for sarcomere assembly, metabolic reprogramming and electrophysiological transitions. Together, our findings define how microenvironmental signals and intrinsic gene programs cooperate to guide heart maturation and establish a broadly applicable framework for functional genomics in complex tissues.

Animals↗

PubMed2026

Transcriptomic analysis of eggs, rediae and cercariae reveal stage-specific adaptations in the rumen fluke Calicophoron daubneyi.

Rumen flukes, particularly the trematode Calicophoron daubneyi, are emerging parasites of livestock in Europe, yet transcriptomic insights into their environmental and intermediate host stages remain limited. Here, we present a comprehensive transcriptomic analysis of eggs at three distinct developmental stages (freshly excreted, early developmental and eye-spot stages), as well as rediae and cercariae, of C. daubneyi. High-quality RNA-sequencing (RNA-seq) datasets revealed both shared and stage-specific transcriptional profiles with each developmental stage exhibiting its own distinct expression pattern. Subsequent GO-Term enrichment analyses revealed that fully embryonated eggs in eye-spot-stage especially upregulated genes related to cilia assembly, movement and motility, reflecting preparation for miracidial hatching and host-seeking behavior. Rediae showed enhanced transcription of genes involved in diverse metabolic and biosynthetic processes, supporting rapid asexual proliferation within the snail intermediate host. Cercariae exhibited predominant upregulation of genes associated with signal transduction and energy metabolism, indicating the adaptation to its changing environmental conditions. These findings provide the first transcriptomic insights into the biology of C. daubneyi outside the definitive host, reveal molecular mechanisms underlying development, transmission and adaptation to a changing environment and identify stage-specific genes as potential targets for interventions aimed at disrupting the parasites life cycle and controlling rumen flukes in the future.

Animals↗