Physiological genomics最新文献

Glycated hemoglobin A1c (HbA1c) indicates average glucose levels over 3 mo and is associated with insulin resistance and type 2 diabetes (T2D). Longitudinal change in circulating HbA1c (ΔHbA1c) is also associated with aging processes, cognitive performance, and mortality. We analyzed ΔHbA1c in 1,886 nondiabetic Europeans from the Long Life Family Study (LLFS) to uncover gene loci influencing ΔHbA1c. Using growth curve modeling adjusted for multiple covariates, we derived ΔHbA1c and conducted linkage-guided sequence analysis. Our genome-wide linkage scan identified a significant locus on 17p12. In-depth analysis revealed a gene locus ARHGAP44 (rs56340929, explaining 27% of the linkage peak) that was significantly associated with ΔHbA1c. Interestingly, RNA transcription of ARHGAP44 was also significantly associated with ΔHbA1c in the LLFS, and this discovery was replicable on the gene locus level in the Framingham Offspring Study (FOS). Taking together, we successfully identified a novel gene locus ARHGAP44 for ΔHbA1c in family members without T2D. Further follow-up studies using longitudinal omics data in large independent cohorts are warranted.NEW & NOTEWORTHY HbA1c is clinically used in T2D diagnosis and monitoring. Its longitudinal change (ΔHbA1c) is associated with T2D-related aging processes and mortality. Targeted association tests under significant linkage peaks in extended families permit identification of unique gene loci. We uncovered a novel gene locus ARHGAP44 for ΔHbA1c with gene-level validations from the FOS and RNAseq data in the LLFS. The finding provides genetically informed biological insight into mechanistic inference of glycemia/HbA1c homeostasis and potential T2D pathophysiology.

Aging is the primary risk factor for the development of many chronic diseases, including dementias, cardiovascular disease, and diabetes. There is significant interest in identifying novel "geroprotective" agents, including by repurposing existing drugs, but such treatments may affect organ systems differently. One current example is the nucleoside reverse transcriptase inhibitor 3TC, which has been increasingly studied as a potential gerotherapeutic. Recent data suggest that 3TC may reduce inflammation and improve cognitive function in older mice; however, the effects of 3TC on other tissues in aged animals are less well characterized. Here, we use transcriptomics (RNA-seq) and targeted metabolomics to investigate the influence of 3TC supplementation on skeletal muscle in older mice. We show that 3TC 1) does not overtly affect muscle mass or functional/health markers, 2) largely reverses age-related changes in gene expression and metabolite signatures, and 3) is potentially beneficial for mitochondrial function in old animals via increases in antioxidant enzymes and decreases in mitochondrial reactive oxygen species. Collectively, our results suggest that, in addition to its protective effects in other tissues, 3TC supplementation does not have adverse effects in aged muscle and may even protect muscle/mitochondrial health in this context.NEW & NOTEWORTHY Recent studies suggest that the nucleoside reverse transcriptase inhibitor 3TC may improve brain health and cognitive function in old mice, but its effects on other aging tissues have not been comprehensively studied. This is the first study to use a multiomics approach to investigate the effects of 3TC treatment on skeletal muscle of old mice. The results suggest that 3TC reverses age-related transcriptomic and metabolite signatures and is potentially beneficial for mitochondrial function in aged muscle.

Defining physiology and methods to measure biological mechanisms is essential. Extensive datasets such as RNA sequencing are used with little analysis of the knowledge gained from the various methodologies. Within this work, we have processed publicly available NCBI RNAseq datasets using a combination of bioinformatics tools for the largest physiological organ, the skin. In many datasets, we identify the quality of the sample, human transcript mapping, the sex of each sample, foreign RNA from bacteria/viruses/protists, and the presence of B/T-cell immune repertoire. Processing 8,274 samples from 132 different experiments for skin samples identifies common flora of skin with elevation of protists (such as Leishmania), bacteria (Staphylococcus, Cutibacterium acnes), and viruses [Human alphaherpesvirus (HSV), Human papillomavirus (HPV)] that may be involved in physiological differences. We observed samples with the Heilongjiang tick virus, human T-cell leukemia virus type I, and equine infectious anemia virus that likely play pathological roles in physiology. Integrating the various biomarkers identified five ideal datasets for skin pathologies that elucidated a novel correlation between the normal skin flora bacterium Bacillus megaterium with major histocompatibility complex (MHC) regulation and the immune repertoire clonal expansion, particularly in patients with hidradenitis suppurativa. Finally, we show that in multiple independent experiments, biological sex is associated with multiple sex chromosome gene differences, highlighting the importance of future work in studying sex differences in skin. Data integrations and multidimensional data mapping are critical for physiological omics advancements, and this work highlights the exciting ability to apply these tools to skin physiology.NEW & NOTEWORTHY Complex bioinformatics mapping to skin RNA sequencing datasets can simultaneously map biological sex, skin-specific genes, bacteria, viruses, protists, and the acquired immune response. The integration of these datasets elucidated bacterial signatures from common skin flora while identifying novel insights on Bacillus megaterium in the acquired immune response and novel viral signatures for Heilongjiang tick virus and equine infectious anemia virus.

Hybrid catfish (Ictalurus punctatus × I. furcatus) is the preferred catfish for US aquaculture due to the heterosis exhibited in many production traits. Improvements in fry production protocols have enabled widespread adoption of these hybrids, with producers using management practices optimized for channel catfish. Research to consider differences, outside of production traits, which may exist between hybrids and their parent species is lacking. Utilizing management practices specifically designed for hybrids may improve production efficiency. The gut microbiome plays critical roles in host development and health and, thus, is relevant to production. In the present study, the microbiota in the anterior, middle, and posterior segments of the intestinal tract were compared between channel and hybrid catfish using high-throughput 16S rRNA gene sequencing. Bacterial community structure was different between channels and hybrids across all intestinal segments (P < 0.05) despite a lack of difference in community diversity. Cetobacterium spp. were found in higher abundances in the middle intestinal segment of hybrids compared with channels (q = 0.02) and found to have a trend of increasing abundance with increasingly distal segments in both channels and hybrids (q < 0.05). Vibrio spp., a low-abundance taxon, was similarly found in higher abundances in the anterior segment of hybrids. These results provide evidence of differences in the gut microbiomes of channels and hybrids and insight into the bacterial communities along the catfish intestinal tract. Additional research will be valuable in understanding why do differences between channel and hybrid catfish exist and how they may contribute to variation in gut microbiome-related production traits.NEW & NOTEWORTHY Hybrid and channel catfish are inhabited by gut bacterial communities of similar overall diversity but of significantly different structure and composition. Cetobacterium spp., a genus previously shown to confer benefits in other hosts, was found in higher abundances in the middle intestinal segment of hybrids and was found to have increasing abundance along the intestinal tract of both channels and hybrids.

Neurodevelopmental disorders (NDDs) are a category of pervasive disorders of the developing nervous system with few or no recognized biomarkers. A significant portion of the risk for NDDs, including attention deficit hyperactivity disorder (ADHD), is contributed by the environment, and exposure to pyrethroid pesticides during pregnancy has been identified as a potential risk factor for NDD in the unborn child. We recently showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin in mice causes male-biased changes to ADHD- and NDD-relevant behaviors as well as the striatal dopamine system. Here, we used an integrated multiomics approach to determine the broadest possible set of biological changes in the mouse brain caused by developmental pyrethroid exposure (DPE). Using a litter-based, split-sample design, we exposed mouse dams during pregnancy and lactation to deltamethrin (3 mg/kg or vehicle every 3 days) at a concentration well below the EPA-determined benchmark dose used for regulatory guidance. We raised male offspring to adulthood, euthanized them, and pulverized and divided whole brain samples for split-sample transcriptomics, kinomics, and multiomics integration. Transcriptome analysis revealed alterations to multiple canonical clock genes, and kinome analysis revealed changes in the activity of multiple kinases involved in synaptic plasticity, including the mitogen-activated protein (MAP) kinase ERK. Multiomics integration revealed a dysregulated protein-protein interaction network containing primary clusters for MAP kinase cascades, regulation of apoptosis, and synaptic function. These results demonstrate that DPE causes a multimodal biophenotype in the brain relevant to ADHD and identifies new potential mechanisms of action.NEW & NOTEWORTHY Here, we provide the first evidence that low-dose developmental exposure to a pyrethroid pesticide, deltamethrin, results in molecular disruptions in the adult mouse brain in pathways regulating circadian rhythms and neuronal growth (MAP kinase). This same exposure causes a neurodevelopmental disorder (NDD)-relevant behavioral change in adult mice, making these findings relevant to the prevention of NDDs.

Preeclampsia is a pregnancy-specific hypertensive disorder and is associated with an increased postpartum risk of cardiovascular morbidity for both women and their offspring. Previous studies have indicated that cord blood endothelial colony-forming cells (ECFCs) are dysfunctional in preeclampsia. The specific mechanisms are not yet fully understood, but dysregulation of alternative splicing has been proposed as one of the pathogenic pathways. To identify specific targets of alternative splicing in fetal ECFCs, we performed transcriptome-wide differential splicing analyses between cord blood ECFCs from preeclamptic (n = 16) and normal pregnancies (n = 13). Selected splicing events were validated using fragment length analysis and Sanger sequencing. In silico transcriptome-wide differential splicing analysis identified a significantly increased abundance of the CADM1 isoform ENST00000542447 in the preeclamptic cohort (P = 0.002), which was confirmed by wet-lab validation. The deleted exon 8 harbors glycosylation sites known to mediate cell-cell adhesion. To investigate the functional impact of alternative splice variants, we induced an in vitro splice switch using antisense morpholino treatment and then monitored cellular effects using migration and angiogenesis assays in ECFCs from six normal pregnancies. The CADM1 exon 8 skipping converted the normal ECFCs to a preeclampsia-like state characterized by a decreased migration ability (P_ANOVA = 0.005) and decreased tubule length (P_ANOVA = 0.02). We propose aberrant splicing of CADM1 and the resulting changes in the adherence properties of ECFCs as a potential contributor to cardiovascular sequelae in the offspring of preeclamptic pregnancies.NEW & NOTEWORTHY We investigated differential splicing between normal and preeclamptic pregnancies in endothelial colony-forming cells (ECFCs) from cord blood. Transcriptome-wide analysis identified exon 8 skipping of CADM1 mRNA to be upregulated in ECFCs from women with preeclampsia. In vitro splice switching studies indicated that induction of this isoform decreases the cell migration and tubule formation abilities of fetal ECFCs. Our findings link a specific splice isoform of CADM1 to preeclampsia, with potential implications for vascular health in the offspring.

Acute cardiorenal syndrome (CRS) represents a critical intersection of cardiac and renal dysfunction with profound clinical implications. Despite its significance, the molecular underpinnings that mediate cellular responses within the kidney during CRS remain inadequately understood. We used single nucleus RNA sequencing (snRNAseq) to dissect the cellular transcriptomic landscape of the kidney following a translational model of CRS, cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in comparison to ischemia-reperfusion injury (IRI). In each dataset, we found that proximal tubule (PT) cells of the kidney undergo significant gene expression changes, with decreased expression of genes critically important for cell identity and function, indicative of dedifferentiation. Based on this, we created a novel score to capture the dedifferentiation state of each kidney cell population and found that certain epithelial cell populations, such as the PT S1 and S2 segments, as well as the distal convoluted tubule, exhibited significant dedifferentiation response. Interestingly, the dedifferentiation response in the distal nephron differed in magnitude between IRI and CA/CPR. Gene set enrichment analysis (GSEA) of PT response to IRI and CA/CPR revealed similarities between the two models and key differences, including enrichment of immune system process genes. Transcriptional changes in both mouse models of acute kidney injury (AKI) highly correlated with a dataset of human biopsies from patients diagnosed with AKI. This comprehensive single-nucleus transcriptomic profiling provides valuable insights into the cellular mechanisms driving CRS.NEW & NOTEWORTHY Cardiac dysfunction is a common cause of acute kidney injury in a malady called acute cardiorenal syndrome. In a mouse model of acute cardiorenal syndrome called cardiac arrest/cardiopulmonary resuscitation, we characterized, for the first time, the kidney transcriptional landscape at the single-cell level. We developed a novel method for quantifying cell response to injury and found that cells adapted through dedifferentiation, the magnitude of which varied depending on cell type.

The study aimed to verify the physiological and metabolic parameters associated with the time to task failure (TTF) during cycling exercise performed within the severe-intensity domain. Forty-five healthy and physically active males participated in two independent experiments. In experiment 1, after a graded exercise test, participants underwent constant work rate (CWR) cycling efforts at 115% of peak power output to assess neuromuscular function (potentiated twitch) pre- and postexercise. Experiment 2 was similar to experiment 1, but with physiological (respiratory parameters, energetic pathway contribution) and metabolic parameters in the blood (gasometry and blood lactate responses) and vastus lateralis muscle tissue (target metabolomic analysis, glycogen content, muscle pH, and buffering capacity in vitro) measured instead of neuromuscular function. Experiment 1 evidenced a significant decrease in muscle force with instauration of peripheral fatigability indices and no change in central fatigue indices. Severe-intensity domain exercise in experiment 2 was accompanied by changes in physiological and metabolic parameters and in blood and muscle parameters. However, the TTF was associated with oxidative contribution (r = 0.811, P < 0.001), as well as anaerobic capacity (r = 0.554, P = 0.027), muscle buffering capacity (r = 0.792, P = 0.035), phosphagen energy contribution (r = 0.583, P = 0.017), and carnitine changes (r = 0.855, P = 0.016), but not correlated with electromyographic response, blood acid-base balance, and muscular glycogen content and pH. TTF during CWR exercise within the severe-intensity domain is likely explained by a combination of interacting mechanisms, with oxidative and phosphagen contributions, and muscle buffering capacity suggested as the main peripheral limiting factors to exercise within this exercise-intensity domain.NEW & NOTEWORTHY For the first time, a metabolomic analysis confirms that the cycling time to task failure (TTF) within the severe-intensity domain can be explained by muscle buffering capacity (62.2%), oxidative pathways contribution (65%), and muscle carnitine changes (71.9%), beyond some correlations with anaerobic capacity, tricarboxylic acid cycle intermediates, and phosphagen pathway contribution. The muscle glycogen content, muscle or blood pH, electromyography, and cardiorespiratory responses were not associated with TTF.

Serum is commonly added to culture medium to improve the production of bovine embryos in vitro. The main goals were to verify the actions of serum to increase blastocyst yield and test the hypothesis that fetal bovine serum alters blastocyst gene expression in a manner that could affect competence to establish pregnancy and dysregulate fetal development. Media used were synthetic oviduct fluid medium bovine embryo 2 (SOF-BE2) and a commercial medium from IVF Biosciences termed here as IVFB. Three experiments were conducted in which either adult or fetal bovine serum (10%, vol/vol) was added at day 1 or 5 of development. Overall, serum increased blastocyst production. Gene expression in blastocysts was measured in the experiment in which fetal bovine serum was added at day 5. Serum resulted in 215 differentially expressed genes for embryos cultured in SOF-BE2 and 194 genes for embryos cultured in IVFB (adjusted P value of <0.05 and a |log₂| fold change >1). Only 24 genes were regulated by serum similarly for both media, including several transcription factors, imprinted genes, PSAT1 implicated in fetal growth in mice, and genes dysregulated in cloned embryos. Serum largely eliminated differences in gene expression between media. Expression data on eight biomarker genes were also used to calculate an embryo competence index previously related to embryo survival. Serum lowered the embryo competence index for both media. In conclusion, actions of fetal bovine serum on the preimplantation embryo include changes in gene expression indicative of reduced embryo competence and possible alterations in fetal development.NEW & NOTEWORTHY Serum is commonly added to the culture medium to improve the production of bovine embryos in vitro, but its molecular consequences for the resultant embryo are unclear. Here, we showed that blastocysts produced in serum experienced changes in gene expression, including transcription factors and imprinted genes. An embryo competence index that predicts embryo's ability to establish pregnancy based on gene expression was reduced by serum, suggesting serum can reduce embryo survivability.