Non-additive interactions between environmental stressors, where biological responses to simultaneous stressors do not equal the sum of individual-stressor responses, commonly occur across organisms and environments. To enable predictions of organismal resilience to shifting patterns of environmental stressors, it is important to both identify these interactions and document the mechanisms underlying them. The supratidal copepod Tigriopus californicus demonstrates a non-additive, antagonistic pattern of increased heat tolerance when simultaneously exposed to high salinities. We investigated salinity's chronic and acute effects on heat tolerance in a northern population and quantified responses in protein abundance to hypersalinity and heat stress, both alone and in combination. The overall proteomic response to multiple stressors was non-additive and largely reflected that to high temperature. However, 42% of multi-stressor proteins were absent from either single-stressor response; we refer to these proteins that are only differentially abundant in the multi-stressor scenario as "emergent". Our results suggest that the increased heat tolerance of T. californicus conferred by hypersalinity may be driven by a combination of these emergent proteins, several proteins induced by hypersalinity in both single- and multi-stressor conditions that may contribute to cross-tolerance, and four proteins with additive abundance patterns (including a small heat shock protein). These candidate proteins play putative roles in several relevant processes including the heat shock response, protein folding, and regulation of metabolism and oxidative stress responses. Our results connect to prior whole-organism findings and highlight promising pathways for future investigation in the context of heat tolerance and multi-stressor interactions.
Background: Sepsis is a life-threatening, infection-triggered syndrome of dysregulated inflammation and immune dysfunction. However, the mechanisms underlying immune escape in sepsis remain poorly understood and merit further investigation. Methods: Gene expression data for sepsis were obtained from the Gene Expression Omnibus (GEO) database: GSE65682 was used to construct the training cohort, and GSE95233 served as an independent validation cohort. Feature genes were screened by integrating differential expression profiling with Weighted Gene Co-expression Network Analysis (WGCNA). A diagnostic model was developed and validated using Receiver Operating Characteristic (ROC) analysis, a nomogram, and decision curve analysis (DCA). Functional enrichment, immune infiltration, and competing endogenous RNA (ceRNA) network analyses were also performed. Finally, consensus clustering was applied to identify molecular subtypes of sepsis. Results: 3 feature genes were identified by differential expression analysis and WGCNA. AUC-based screening selected 2 diagnostic genes (NXT1 and UXS1), which demonstrated high diagnostic accuracy (AUC > 0.9). Immune infiltration analysis revealed distinct patterns between the Sepsis and Control groups. Regulatory network analysis identified key miRNAs targeting these 2 genes and lncRNAs that regulate those miRNAs. 2 sepsis subtypes with distinct immune and molecular characteristics were further identified. Conclusion: This study systematically explored the association between immune escape and the pathogenesis of sepsis and, through the integration of multiple bioinformatics approaches, elucidated the immune microenvironmental characteristics and molecular regulatory mechanisms of the disease, providing new insights into understanding its pathophysiology and developing targeted diagnostic and therapeutic strategies.
Researchers have posited that increased consumption of tea and coffee may be associated with more favourable treatment outcomes in patients with age-related macular degeneration (AMD). However, there is no clear evidence regarding the causal associations. To delve deeper into this potential connection, scientists employed a rigorous method known as Mendelian randomization (MR). This technique was utilized to explore the causal impact of tea and coffee consumption on the development or progression of AMD. With the aim of investigating the cause-effect relationship between 16 tea and coffee consuming subtypes and 3 AMD, we designed a two-sample MR-study using comprehensive data from genome-wide association studies (GWAS). The major approach adopted was inverse variance weighting (IVW). Furthermore, we implemented complementary methods like the weighted median (WM), weighted mode, and MR-Egger to strengthen our findings. Sensitivity analyses, including MR-Egger, MR-PRESSO, leave-one-out, and Cochran's Q tests, were employed to validate results, explore heterogeneity and pleiotropy, and pinpoint potential biases. 268 instrumental variables were selected for MR analysis. The results showed that standard tea intake may be a protective factor for wet AMD (OR=0.7076, 95%CI=(0.5776 - 0.8668), P=8×10-4, PFDR=0.0402). Sensitivity analysis suggests that the results are robust. Our findings provide genetic evidence that standard tea intake is a protective factor against wet AMD, providing new insights into early risk stratification and prevention strategies for the disease.
Glucocorticoids (GCs), such as cortisol, bind to receptors in most tissues, triggering a stress response that enables individuals to adapt to stressors physiologically and behaviorally. GC signaling has been associated with plastic, stress-induced epigenetic modifications. However, the epigenetic profiles of individuals with divergent cortisol reactivity before and after a common challenge test have rarely been considered. Cortisol levels were measured in the blood plasma of 400 European seabass (Dicentrarchus labrax) to select 80 individuals exhibiting low- and high-responsiveness phenotypes. Weight, lysozyme activity, and plasma glucose and lactate levels were also measured. The methylome of blood samples from these individuals was investigated at 41,132 CpG positions before and after a 3-mo stress challenge test. We identified 273 differentially methylated cytosines, which mapped to 159 annotated differentially methylated genes (DMGs). We categorized differential methylation as "constitutive" or "induced," distinguishing between the two phenotypes in pre- and post-stress situations, respectively. Methylation observed at DMGs may also remain hypo- or hypermethylated in both contexts; however, seven of these showed a rewiring from hypo- to hypermethylation. Many DMGs are relevant to GC signaling, connecting to the non-genomic and genomic actions of cortisol. They can be considered as stress biomarkers monitored in the blood of this highly-prized species. Although our current study has limitations, we demonstrate the potential of a genome-wide epigenetic approach to studying endocrine divergence between stress-responsive fish phenotypes.NEW & NOTEWORTHY The association of DNA methylation with glucocorticoid signaling has attracted considerable interest. However, studies investigating genome-wide methylation differences in individuals with different cortisol responses before and after exposure to stress have been overlooked. Here, we demonstrate that the blood methylomes of fish with distinct cortisol responsiveness exhibit distinct pre-and post-stress methylation profiles, indicative of the cellular and organismal actions of cortisol possibly triggering the adaptive stress response of each phenotype in the face of stress.
In teleosts, insulin-like growth factor-binding protein-2b (IGFBP-2b) is the major carrier of serum insulin-like growth factor (IGF). A line of gene-edited rainbow trout (2bKO) was produced that lacks a functional IGFBP-2b and associated phenotypes of reduced serum IGF-1, increased appetite, and faster growth compared with wild-type controls (WT). Transcriptomic analysis was completed in liver and muscle from fed and feed-deprived fish from the 2bKO and WT line; the differentially expressed gene (DEG) profiles were used to identify biological functions and pathways affected by the loss of IGFBP-2b and predict IGF-dependent and IGF-independent mechanisms regulated by IGFBP-2b. In general, DEGs reflected downregulation of hepatic functions and signaling pathways in 2bkO liver, whereas an overall upregulation was observed in muscle. A predicted increase in IGF-1 signaling in muscle of fed fish likely facilitated an upregulation in myogenic mechanisms. IGF-independent responses in both liver and muscle are consistent with IGFBP-2b interacting with Type II, III, and IV nuclear receptors such as hepatocyte nuclear factor 4A, thyroid hormone receptor, liver X receptor, and pregnane X receptor, thus mediating changes in lipid, glucose, and sterol metabolism. In the liver, immune and cytokine systems were inhibited (tumor necrosis factor-α, nuclear factor-κB, and interleukin-1B), supporting that IGFBP-2b may play a central role to regulate the cross talk between systems that modulate the balance of energy between growth and immune function. In summary, through both enhanced IGF-1 signaling and regulation of IGF-independent mechanisms, it is predicted that the loss of IGFBP-2b increased muscle growth and regulated nutrient metabolism and cytokine signaling, providing insight into the functional role of IGFBP-2b in rainbow trout.NEW & NOTEWORTHY Gene expression profiles predict IGFBP-2b as a regulator of ligand-dependent nuclear receptors (LDNRs) in rainbow trout, supported by protein modeling that infers interactions between IGFBP-2b1 and specific LDNRs. Additional IGF-independent responses include upregulation of cytokine and transforming growth factor-B1 signaling in hepatic tissue. Through its dual control of IGF-dependent and IGF-independent processes, IGFBP-2b1 may be a mechanism for integrating signals that direct energy toward growth or divert energy to support an immune response.
Hypercapnia occurs in numerous clinical conditions, both acutely and chronically. We previously demonstrated in healthy goats that chronic hypercapnia (CH) produced by exposure to elevated inspired CO2 leads to a sustained increase in minute ventilation, despite dynamic changes in acute CO2 sensitivity across the first week of exposure. Specifically, steady-state ventilation increased during CH, whereas acute CO2 sensitivity was transiently blunted at 24 h and returned toward baseline after 7 days. These findings suggest that ventilatory acclimatization to CH is not solely explained by changes in acute CO2 sensitivity or by traditional mechanisms of neuroplasticity within the respiratory network. To further explore the tissue-level responses to CH in the cardiorespiratory network, we performed bulk-tissue RNA sequencing on medullary brainstem regions involved in cardiorespiratory control. We hypothesized that CH would induce time- and region-dependent transcriptomic responses during the period when ventilatory acclimatization occurs. Differential expression analyses revealed dynamic, region-specific transcriptomic changes at 3 hours (h), 24 h, and 7 days of CH. At 3 h, differentially expressed genes were enriched in vascular- and endothelial-associated gene ontology terms. By 24 h, genes within the nucleus tractus solitarius (NTS)/dorsal motor nucleus of the vagus (DMV) and ventral respiratory column (VRC) were associated with mitochondrial function were broadly downregulated, particularly transcripts related to mitochondrial respiratory complexes and oxidative phosphorylation. At 7 days, relatively few differentially expressed genes were detected. These findings suggest a time- and region-dependent tissue-level transcriptional response to CH. Data reported herein highlight vascular- and mitochondria-associated pathways as candidates for future mechanistic studies of physiological adaptation to chronic CO2 exposure.NEW & NOTEWORTHY Chronic hypercapnia elicited time- and region-dependent tissue-level transcriptomic responses in brainstem regions involved in cardiorespiratory control. At 3 h, differentially expressed genes (DEGs) were enriched in vascular- and endothelial-associated GO terms. At 24 h, mitochondria-associated transcripts were downregulated within the NTS/DMV and VRC. By 7 days, few DEGs were detected. These findings reveal novel, temporally distinct transcriptional responses to CH and identify vascular- and mitochondria-related pathways for future studies of physiological acclimatization to chronic hypercapnia.
Allergen and nanoparticle exposure generate reactive oxygen species (ROS) that endanger genome integrity, yet airway epithelial cells survive repeated exposures. Here we show that environmental allergens from Alternaria alternata and polyethyleneimine (PEI) nanoparticles induce oxidative stress, triggering the rapid release of double-stranded DNA fragments enriched for repetitive elements (SINEs, LINEs, and LTRs), centromeric sequences, and late-replicating, origin-poor fragile site-containing genes. Nanopore sequencing, along with a multiomics approach, was used to analyze fragments of extracellular DNA (eDNA) in human and mouse airway epithelial cells and bronchoalveolar lavage fluid from mice. We show that eDNA release following Alternaria or PEI exposure produces similar genomic sequence profiles, suggesting that a mechanism exists to selectively export these fragments out of the nucleus and into the airway lumen. However, epigenomic modifications localized around transcriptionally active regions differed between Alternaria and PEI exposures, with potentially lasting implications for gene expression and function in airway epithelia. We propose that export of DNA fragments is selective to reduce repetitive DNA fragment accumulation and secondary structure formation in the nucleus, thus ensuring airway epithelial cell survival.NEW & NOTEWORTHY Exposure of airway epithelia to environmental allergens or nanoparticles invokes a novel genome-protective physiological response to oxidative stress. Fragments of double-stranded genomic DNA released into the airway lumen originate from repetitive, transcriptionally active, and fragile sites within the genome. Exporting DNA with high repetitive content potentially aids cell survival through the preservation of genome integrity and fidelity during the repair process.
Precise coordination of parturition and fetal organ maturation is critical for neonatal survival. In sheep, a fetal cortisol surge, triggered by hypothalamic-pituitary-adrenal (HPA) axis activation, drives organ maturation and placental estradiol (E2) synthesis to promote labor, but the upstream signals initiating this cascade remain unclear. We tested whether maternal E2 administration at physiological levels alters fetal endocrine and pulmonary maturation through transcriptional regulation. Pregnant ewes (139-142 days gestation) received Silastic implants containing E2 (200 mg; n = 6) or empty controls (n = 6). Fetal hypothalamus, pituitary, adrenal, and lung tissues were collected 26 h post treatment for RNA sequencing; lung samples also underwent immunohistochemistry, and maternal, fetal, and umbilical plasma were analyzed for hormones. Maternal E2 increased approximately fourfold (P < 0.01), whereas fetal and umbilical E2 remained unchanged. Transcriptomic responses were strongest in the pituitary (914 differentially expressed genes, DEGs), followed by lung (150), adrenal (16), and hypothalamus (6) (FDR ≤ 0.1, |log2FC| ≥ 1). Pituitary responses included pro-opiomelanocortin (POMC) downregulation and enrichment of neurogenesis, axon guidance, and cell adhesion pathways. The hypothalamus showed enrichment for hormone secretion, neuroendocrine regulation, and estrogen signaling. In the lungs, ERα-positive nuclei increased (P = 0.04), whereas surfactant proteins A and C were unchanged. These findings demonstrate that maternal E2, without altering fetal circulating E2, induces tissue-specific fetal transcriptomic changes consistent with endocrine and pulmonary maturation. Maternal E2 may therefore contribute to fetal readiness for birth through indirect mechanisms acting independently of, or in concert with, fetal cortisol.NEW & NOTEWORTHY Successful birth requires precise coordination between fetal organ maturation and the hormonal signals that trigger labor. Using a sheep model, we show that maternal estradiol (E2) administered at physiological levels induces broad transcriptomic changes in fetal endocrine and pulmonary tissues without altering fetal circulating E2 levels. These findings highlight a previously unrecognized role for maternal estrogen in modulating fetal development, suggesting alternative or complementary pathways to cortisol in preparing the fetus for birth.
Obesity arises from the complex interplay between genetic and epigenetic factors, with developmental programming shaping adipose fate, energy homeostasis, and treatment responses later in life. Findings from the developmental origins of health and disease (DOHaD) framework reveal that prenatal factors-such as maternal nutrition, adiposity, hyperglycemia, smoking, and stress-and early exposures imprint dynamic epigenetic marks-DNA methylation, histone modifications, and noncoding RNAs-on key tissues (adipose and hypothalamic circuits), which are associated with both childhood and adult adiposity. These marks contribute to an "epigenetic memory" that exhibits a graded decay model rather than absolute permanence, yet persists even after weight loss, limiting full reversibility of the obese phenotype. This phenomenon is supported by transcriptional and epigenomic profiles of human and mouse adipose tissue following weight loss. In obesity, adipose niche remodeling involves chronic inflammation, fibrosis, and macrophage-fibroblast interactions within "crown-like" structures, with OSM-MINCLE circuits modulating fibrosis. In prevention and therapy, combining lifestyle interventions with dual- or selective-incretin-based drugs results in significant weight loss and improves body composition and muscle function. Beyond classical metabolic targets, several anti-obesity drugs-including metformin, thiazolidinediones, GLP-1 agonists, SGLT2 inhibitors, and nutraceuticals such as resveratrol-also exert epigenetic remodeling effects in liver, muscle, and adipose tissue, although clinical evidence for some nutraceuticals remains limited by bioavailability. Integrating epigenetic biomarkers with critical developmental windows, together with digital health and personalized medicine, could optimize risk stratification and refine our understanding of obesity as a modifiable, yet path-dependent biological condition.
Akkermansia muciniphila, a commensal bacterium that represents 1-4% of the fecal microbiota in healthy adults, and can use mucin as a sole source of carbon and nitrogen, has attracted interest as soon as it was discovered due to the relationship between its abundance and various benefits, particularly pertaining to metabolic health. Especially noteworthy is the finding that A. muciniphila stimulates the proliferation and differentiation of intestinal stem cells, as part of tissue homeostasis and repair after biological, chemical, or physical injury. In this review, we discuss some of the evidence that supports the ability of A. muciniphila and of specific bacterial proteins to support the intestinal stem cell niche. The additional finding that some of these benefits are exerted during gestation on fetal stem cells, persist into adulthood, and influence crypt regeneration after injury, suggests that A. muciniphila may be part of the gestational environment that shapes the health of offspring. While most A. muciniphila health benefits were characterized using MucT (A. muciniphila ATCC BAA-835), the discovery of large phylogenetic and functional diversity within the Akkermansia genus galvanized efforts to compare different strains for their individual health profiles. Even closely related A. muciniphila strains may not always share the same health benefits, and sometimes the same strain may be beneficial or harmful depending on host-related factors, pointing towards the need to characterize health phenotypes at the strain level and in context of the host, and underscoring the ongoing gaps in defining the optimal formulation and safety profile of individual strains.
Decompression sickness (DCS) is a pathology caused by the appearance of gas emboli in the bloodstream and tissues. However, the weak correlation between the amount of venous gas emboli (VGE) and the development of DCS, as well as the considerable interindividual variability in DCS susceptibility, suggests that a higher DCS resistance could be associated with a better management of VGE-induced stress. To study the effects of VGE independently of the hyperbaric stress induced by diving, Wistar and DCS-resistant male and female rats received 5 mL/kg of a 0.9% NaCl solution containing air microbubbles through the tail vein. After 120 min, the liver and lungs were harvested. Wet-to-dry weight ratio was determined in the lungs. Gene expression was quantified by reverse transcription-polymerase chain reaction in the liver. Compared with standard Wistar, DCS-resistant rats exhibited a lower lung wet-to-dry weight ratio after air microbubble injection, suggesting lower pulmonary fluid accumulation. In the liver, DCS-resistant rats showed higher tissue factor transcription at the basal state and post-air microbubble injection. Tissue factor pathway inhibitor was lower in DCS-resistant rats at the basal state but higher following air microbubble injection. Levels of heat shock protein 70 (HSP70), heat shock protein 27 (HSP27), and early growth response 1 (Egr-1) were higher in DCS-resistant rats after air microbubble injection. At the basal state, only HSP27 was higher in DCS-resistant rats, with HSP70 lower and Egr-1 not different. These results help clarify the pathways involved in the response to VGE and highlight potential mechanisms underlying resistance to DCS, including enhanced anticoagulant pathways and improved cellular stress responses.NEW & NOTEWORTHY This study suggests for the first time that DCS resistance may be associated with a better tolerance to VGE. This greater DCS resistance could be achieved through improved control of the procoagulant effects of bubbles via TFPI-dependent inhibitory mechanisms and an enhanced cellular stress response to VGE by HSP70, HSP27, and EGR-1. It also suggests that it may be possible to stratify the individual DCS risk based on the thromboinflammatory response to bubbles.
Genome-wide association studies (GWASs) are commonly used to investigate the genetic basis of complex traits. However, to be adequately powered, they typically require large sample sizes to provide precise inferences. To address this challenge, this article introduces genomic informational field theory (GIFT), a novel data-analytic method that enhances the power of genetic analyses, enabling the use of smaller datasets without compromising precision. In a small cohort of 157 ponies, GIFT was applied to examine the complex trait of "height at withers," comparing its performance to traditional GWAS. GIFT enabled the identification of genetic loci linked to insulin physiology, validating, in turn, a long-standing hypothesis that "height at withers" is associated with insulin physiology in equids, potentially promoting equine metabolic syndrome (EMS). By redefining correlations between single-nucleotide polymorphisms (SNPs), GIFT provides new insights into linkage disequilibrium and reveals underlying gene network structures. This, in turn, enables the distinction between core and peripheral genes within these networks. By reducing the time and cost associated with large-scale genotype-phenotype mapping studies without sacrificing statistical robustness, GIFT broadens access to quantitative genetic research, allowing smaller-scale studies to investigate the genetic architecture of complex traits with greater resolution.NEW & NOTEWORTHY Inferring genotype-phenotype associations typically requires large sample sizes, limiting many genetic studies. Genomic informational field theory (GIFT), a novel data-analytic tool, overcomes this by enabling accurate association mapping in small datasets. We further show how GIFT's extended framework infers linkage disequilibrium and gene networks, distinguishing core from peripheral genes involved in complex traits. This advancement enhances understanding of biological architecture and enables high-resolution genetic research in limited cohorts, offering a powerful, cost-effective alternative to traditional large-scale approaches.
Sensory systems of many organisms display periodic adjustments to accommodate cyclical changes in the local environmental conditions. Seasonal fluctuations in visual perception are documented in many species, including humans, but the mechanisms and ecological significance of these adaptations often remain obscure. Despite limited knowledge of bat visual ecology relative to hearing, the diversity of bat species makes them useful models for studying sensory adaptation mechanisms. Here, we analyze daily and seasonal changes in gene expression in the eyes of a temperate echolocating bat, the Mexican free-tailed bat (Tadarida brasiliensis). A total of 44 wild-caught bats were sampled from the same location across all four seasons, with whole eyes sequenced for total mRNA expression. Expression patterns were analyzed using differential expression analysis and clustering techniques for identifying correlation networks and evidence of cyclical enrichment. In addition, a target gene list representing key physiological processes was applied to assess which biological pathways displayed the most robust seasonal or daily changes. About 17.8% of genes showed significant differential expression based on season, compared with 11.5% of genes for daily expression. Several gene networks related to the circadian clock, phototransduction, and metabolic function displayed significant rhythmic seasonal effects. Quantum catch modeling indicates higher photon capture potential in summer based on weighted opsin expression, consistent with an adaptive response to lower twilight irradiance. Seasonal remodeling of the ocular transcriptome is consistent with enhanced phototransduction in summer, suggesting vision may play a greater role during this period.NEW & NOTEWORTHY The visual ecology of insectivorous bats remains obscure due to challenges studying their natural behaviors in the wild. Using functional genomics, we can identify physiological changes that may highlight when vision matters most for bats. Our results reveal a dynamic sensory response to environmental light, with visual sensitivity optimized for summer twilight. This study provides the first evidence of seasonal plasticity in bat vision and underscores the importance of studying nonmodel species in natural contexts.
Hypertension is a progressive condition that predisposes patients to the development of chronic kidney disease (CKD). Previous genetic and animal studies utilizing the Dahl salt-sensitive (SS) rat, a genetic model of progressive hypertension and CKD, identified that Arhgef11 was playing a role in hypertension and CKD in the Dahl SS model. Arhgef11 is a Rho guanine nucleotide exchange factor involved in the regulation of the cytoskeleton, intracellular trafficking, protein-protein interactions, and transcription factor regulation. Temporal evaluation of SS-wild type (WT) and SS-Arhgef11-/- rats demonstrated that the loss of Arhgef11 attenuated hypertension and improved renal function. Transcriptome and proteomic studies lead to the hypothesis that dysregulation of these pathways in the kidney, particularly the proximal tubule, may alter sodium handling and ultimately lead to hypertension. Current rat studies confirmed previous work between SS-WT and SS-Arhgef11-/- and investigated early (week 4) transcriptional changes using single-nuclei RNA sequencing, present before blood pressure differences are observed. Due to only being able to test systemic loss of Arhgef11 in the rat model, a global knockout [Arhgef11-/-(CMV)], as well as a proximal tubule-specific deletion [Arhgef11-/-(Sglt2)] were studied in the mouse. Studies utilized two models of experimental hypertension: Angiotensin II and deoxycorticosterone acetate (DOCA) + salt. Both models demonstrated a slight protective effect on blood pressure and kidney injury for DOCA experimental models, replicating the rat knockout data. However, the impact of the loss of Arhgef11 was dependent on the type of induced hypertension, with the large effect in the rat model likely explained by the highly permissive genetic background of the Dahl SS model.NEW & NOTEWORTHY The present study tests the hypothesis that Arhgef11, specifically within the context of experimental hypertension (AngII or DOCA), plays a role in regulating blood pressure at the systemic or kidney-specific level. A slight protective effect on blood pressure and kidney injury for DOCA knockout models was observed, replicating the rat knockout. However, the large effect in the rat model is likely explained by the highly permissive genetic background of the Dahl SS model.
Hypertrophic cardiomyopathy (HCM) is the leading genetic cause of heart disease. Although research has been focused on HCM for the past several decades, clinical treatments for patients remain limited. The heart comprises several myofilament proteins that work together to facilitate proper contraction and relaxation to pump blood throughout the body. Cardiac myosin binding protein-C (cMyBP-C) is a thick-filament regulatory protein, and mutations in cMyBP-C are frequently linked with clinical cases of HCM. To further understand the role of cMyBP-C and its contribution to cardiac disease, we assessed the progressive development of molecular and morphological biomarkers associated with HCM in a cMyBP-C knockout mouse model. We assessed gene expression associated with hypertrophy, fibrosis, and sarcomeric proteins at 21, 60, and 183 days of age via a custom NanoString nCounter gene panel designed from clinically relevant human cardiac disease panels. Cardiac morphology and tissue remodeling were evaluated using biochemical and histological assays. Our findings unveil significant dysregulation in genes associated with hypertrophy and fibrosis in cMyBP-C deficient mice at 21 days old, which precedes irreversible overt fibrosis in the cardiac tissue. However, changes in sarcomeric gene expression only appeared after hypertrophy and fibrosis were established. The early changes in gene expression underscore the need for better understanding the mechanisms driving HCM development, which may offer potential avenues for therapeutic intervention before pathological remodeling occurs. Pharmaceutical interventions that target cardiac dysfunction may be most effective before cardiac remodeling, highlighting the potential utility for early screening and preventative strategies to manage genetic-based cardiomyopathies. NEW & NOTEWORTHY The effect of cMyBP-C ablation in the cardiac sarcomere induces cell-signaling changes that precede significant overt fibrosis. These data indicate that early clinical screening may allow for treatment before irreversible, pathological remodeling of the heart takes place.
