Physiological genomics最新文献

In a randomized, dose-response trial, we used molecular and phenomic profiling to compare responses with traditional moderate-intensity endurance and resistance training (TRAD) versus high-intensity tactical training (HITT) that encompassed explosive whole-body interval training and high-intensity resistance training. Ninety-four participants (18-27 yr) completed 12 wk of TRAD or HITT followed by 4 wk of detraining. Although similar performance and body composition improvements were observed in response to HITT and TRAD, some dose-dependent differences were observed for: 1) ex vivo muscle tissue changes in myofiber size, capillarization, satellite cell frequency, and mitochondrial function and 2) differential gene expression (DGE) of muscle and serum exosomal miRNAs (miRs). However, these dose-dependent ex vivo muscle adaptations were overshadowed by wide-ranging interindividual response heterogeneity (IRH). We therefore explored response heterogeneity by first establishing minimum clinically important difference (MCID) scores to classify each participant based on MCIDs for functional muscle quality (fMQ) and cardiorespiratory fitness (CRF) and then modeling all data based on MCID classification. Using higher-order singular value decomposition (HOSVD), we established multidimensional biocircuitry linked to interindividual response heterogeneity that identified the most influential features across lifestyle, body composition, performance, ex vivo muscle tissue, and miRNA mapping domains. Via cross-comparison of MCID-linked miRs identified via DGE and HOSVD, nine miRs emerged as robust features of training adaptability, providing new insights into the integrated biocircuitry driving IRH.NEW & NOTEWORTHY We examined in vivo and ex vivo adaptations to traditional moderate-intensity endurance and resistance training (TRAD) versus high-intensity tactical training (HITT; explosive whole-body interval training and high-intensity resistance training). TRAD and HITT improved physiological performance and body composition, and induced ex vivo muscle adaptations, with remarkable interindividual response heterogeneity (IRH) in improvements. We leveraged multidimensional modeling to identify interindividual response heterogeneity biocircuitry that integrates deep phenotyping and miR transcriptomics (serum exosomes and skeletal muscle).

The homocysteine-methionine cycle is involved in the critical human cellular functions, such as proliferation and epigenetic regulation. S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolites are synthesized in this metabolic cycle, and their levels are finely regulated to ensure proper functioning of key enzymes controlling the cellular growth and differentiation. SAM and SAH levels were found altered in the plasma of subjects with trisomy 21 (T21), but how this metabolic dysregulation influences the clinical manifestation of T21 phenotype has not been previously described. SAM and SAH quantifications were performed in urine samples of 58 subjects with T21 and 48 controls (N) through liquid chromatography with tandem mass spectrometry. SAH resulted slightly more excreted in urine of subjects with T21 (T21/N mean ratio = 1.16, P value = 0.021), although no difference was found in SAM levels. Metabolite urine levels were compared with those previously observed in plasma, in which higher amounts of SAM and SAH were found. In addition, we examined if an association between the levels of SAM and SAH in T21 and the expression levels of genes involved in their production/utilization exists using the transcriptome map of blood samples of T21 and N subjects. The analysis showed overexpression of 44 methyltransferase genes responsible for the conversion of SAM to SAH, of two genes involved in SAH utilization, adenosylhomocysteinase-like 1, adenosylhomocysteinase-like 2, and of one gene involved in SAM utilization, adenosylmethionine decarboxylase 1. These data support the hypothesis that T21 genetic imbalance is responsible for SAM and SAH excess, which may be involved in the T21 phenotypic features.NEW & NOTEWORTHY S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are critical metabolites for the fundamental cellular functions, such as proliferation and epigenetic regulation. For the first time, their levels were quantified in the urine of subjects with trisomy 21 (T21) and compared with euploid controls (N). These dosages were compared with their plasma levels, and the expression of genes involved in SAM and SAH production/utilization was further investigated in the differential blood transcriptome map of T21 versus N samples.

Immunotherapy is often thwarted by the innate ability of cancer to evade immune detection. Lysine-specific demethylase 1A (KDM1A/LSD1) has been implicated in the development of various cancers, yet its specific influence on immune evasion in lung cancer and the mechanisms at play are not well defined in the current scientific discourse. Through bioinformatics, we probed the expression patterns of KDM1A and fibrinogen-like protein 1 (FGL1) in lung cancer continues with cellular validation. Lactate dehydrogenase (LDH) and enzyme-linked immunosorbent assay were used for the assessment of CD8⁺ T-cell responses to tumor cells. To uncover the molecular underpinnings, we use a suite of techniques including bioinformatics, luciferase reporter assays, chromatin immunoprecipitation, and qRT-PCR. Bioinformatics pointed to a positive relationship between KDM1A and FGL1, with both markers highly expressed in lung cancer. KDM1A was found to dampen the cytotoxicity of CD8⁺ T cells toward lung cancer cells through its transcriptional activation of FGL1. Our work reveals the role of KDM1A in lung cancer immune evasion by transcriptionally activating FGL1, which could inform the design of new immunotherapies.NEW & NOTEWORTHY KDM1A and FGL1 exhibit high expression in lung cancer. KDM1A expression is associated with immune evasion in tumors. KDM1A regulates FGL1, thereby influencing the antitumor activity of CD8⁺ T cells in lung cancer.

Heat stress (HS) in cattle significantly challenges the dairy industry by reducing milk production. However, the molecular mechanism behind mammary gland responses to HS and recovery remains poorly understood. This study aimed to determine the transcriptomic changes in lactogenic-like bovine mammary epithelial (MAC-T) cells after HS and post-HS recovery. Six culture conditions were analyzed: MAC-T cells cultured in basal medium, cells in lactogenic medium to induce differentiation, differentiated cells at standard temperature (37°C) or HS (42°C) for 1 h. HS cells were collected after incubation at 37°C for either 2 or 6 h to examine the extent of recovery. A total of 1,668 differentially expressed genes were identified. Differentiated cells expressed genes associated with milk lipid synthesis, indicating lactogenic potential. HS suppressed genes involved in cellular differentiation and activated heat shock protein genes. Several transcription factors were identified as potential regulators of HS response. During recovery, chaperon-mediated protein folding genes remained elevated. Apoptosis regulation genes were induced at 2 h, and cellular homeostasis regulation genes were enriched at 6 h. Overall, these findings provide insight into the transcriptomic response of MAC-T cells to heat stress and recovery under in vitro conditions, offering a foundation for future studies on cellular responses to environmental stressors.NEW & NOTEWORTHY Bovine mammary epithelial (MAC-T) cells were differentiated (D), heat stressed (HS), and recovered (R) under different conditions. Differentiated cells expressed milk lipid synthesis genes, which were repressed by HS. Further, HS upregulated heat shock protein genes and altered several transcription factors involved in HS response. Recovery after HS-induced apoptosis regulation at 2 h and cellular homeostasis regulation at 6 h.

How environmental conditions during embryogenesis shape development, physiology, and phenotype is a key question for understanding the roles of plasticity and environmental factors in determining organismal traits. Answering this question is essential for revealing how early-life environmental variation drives adaptive responses and influences evolutionary processes. Here we examine how hypoxia impacts cardiac gene expression during embryonic development in the American alligator (Alligator mississippiensis). Eggs were incubated in normoxic (21% O₂) or hypoxic (10% O₂) conditions from 20% to 90% of embryogenesis. Embryos were sampled at 70% and 90% of development to measure gene expression, embryo mass, and organ mass. Hypoxia significantly restricted embryonic growth while enlarging hearts and brains relative to body size. Gene expression analyses show that hypoxia led to upregulation of 182 genes and downregulation of 222 genes, which were enriched in pathways related to muscle contraction, oxygen transport, protein catabolism, and metabolism. Developmental changes in 3,544 genes were associated with cell division, extracellular matrix remodeling, and structural organization. Functional and network analyses highlighted hypoxia-induced shifts in cardiomyocyte physiology, suggesting adaptations to enhance cardiac performance under low oxygen availability. Despite hypoxia-related downregulation of sarcomere and metabolic genes, hypertrophic responses were evident, consistent with previous findings of improved cardiac function in hypoxia-exposed juveniles. Collectively, our findings offer new genome-wide insights into the effects of hypoxia on the embryonic alligator heart, uncovering significant adaptive developmental plasticity. These results have broad implications for understanding how environmental factors shape cardiovascular phenotypes and drive evolutionary responses to hypoxia in reptiles.NEW & NOTEWORTHY This study investigated the impact of hypoxia on the cardiac transcriptome in alligator embryos. Exposure to low oxygen levels induced significant changes in gene networks controlling cardiac contraction, protein catabolism, oxygen transport, pyruvate metabolism, and adrenergic signaling. Ontogenetic changes suggest slowing of cell proliferation and remodeling of the extracellular matrix in the heart as embryos approach the end of incubation. This study provides the first characterization of myocardial gene expression patterns in developing alligator hearts.

Tumor microenvironment (TME) plays an important role in tumorigenesis, development, metastasis, and drug sensitivity, but little is known about it in lung squamous cell carcinoma (LUSC). Here, the RNA-sequencing data, clinical and survival data of patients with LUSC in The Cancer Genome Atlas, and six independent datasets were collected. Based on the unsupervised clustering of knowledge-based functional gene expression signatures, LUSC was classified into four subtypes. Cluster 1 and cluster 3 exhibited substantial tumor immune infiltration, suggesting a better response to immunotherapy. Relatively worse survival was observed in cluster 4, probably due to higher angiogenesis. Besides, differentially expressed genes in cluster 1, cluster 2, and cluster 3 were prominently enriched in immune-related pathways, whereas extracellular matrix-related pathways were enriched for cluster 4. Genomic data analyses showed significant variations in tumor mutational burden and mutational frequency of several genes, such as tumor protein P53 (TP53), among the four subtypes. In addition, the four subtypes exhibited heterogeneity in the sensitivity of commonly used chemotherapy drugs for lung cancer and the intratumor microbiome profile. Finally, a prognostic model was developed, and its performance and generalization ability were independently validated in multiple datasets. Overall, our study advances the understanding of the TME in LUSC and proposes a prognostic model that facilitates clinical decision-making.NEW & NOTEWORTHY This study obtained four immunological subtypes exhibiting substantial difference in the tumor microenvironment (TME), immune-related pathways, tumor mutational burden, drug sensitivity, and intratumor microbiome. Furthermore, we developed a novel prognostic model consisting of 11 signature genes showing excellent performance in predicting prognosis. Our study deepens the understanding of the heterogeneity of the TME in lung squamous cell carcinoma (LUSC) and contributes to the precision therapy of patients with LUSC.

Over 40% of Samoans have at least one copy of the minor A allele at rs373863828 in encoding CREB3 regulatory factor (CREBRF), which is associated with increased body mass index (BMI) but decreased odds of type 2 diabetes mellitus. The mechanisms underlying this paradoxical effect remain unknown. We hypothesized that gut microbiota may play a role and examined associations between CREBRF genotype and gut microbial diversity and composition among Samoan infants. Fecal samples were collected from Samoan infants aged 0 (n = 23), 4 (n = 20), and 21 (n = 27) mo. Microbiota community structure was analyzed using 16S rRNA bacterial gene sequencing. Both cross-sectional and longitudinal analyses revealed no associations between CREBRF genotype and overall microbiome composition or diversity at 0 or 4 mo. Cross-sectional analysis at 21 mo revealed a significant association between genotype and unweighted UniFrac distances (F_1,24 = 1.855, R² = 0.072, P = 0.015). Longitudinal differential abundance analysis also revealed several differentially abundant taxa at 21 mo. Notably, the AG genotype was associated with a lower relative abundance of Escherichia-Shigella (β = -6.741, SE = 2.243, P = 0.004, q = 0.042). Significant genotype differences in gut microbiome composition and diversity at 21 mo suggest that gut microbiota may be involved in relationships between CREBRF genotype and metabolic health. No genotype differences were observed at 0 or 4 mo, suggesting that environmental and/or maternal variables have a greater influence on the gut microbiome in early infancy, and genotype effects emerge later. Further research should examine whether genotype differences in gut microbiota are associated with functional differences in metabolic or immune signaling pathways or energy extraction.NEW & NOTEWORTHY Missense variant rs373863828 in CREBRF is associated with higher odds of obesity but lower odds of diabetes among Polynesians. We examined associations between CREBRF genotype and gut microbial diversity and composition among Samoan infants and identified significant differences at age 21 mo but not at age 0 or 4 mo. These results suggest that gut microbiota may contribute to the mechanisms through which CREBRF genotype impacts metabolic health.

While exercise performance deteriorates in hot environments, heat stress may contribute to exercise-induced adaptations in skeletal muscle. In this study, we assessed transcriptional profiles of equine skeletal muscle following 3 min of high-intensity exercise (at the speed eliciting their maximal oxygen uptake) in cool [wet bulb globe temperature (WBGT) 15°C] or hot (WBGT 30°C) conditions. Differential gene expression was identified using DESeq2 (false discovery rate cutoff: 0.05, minimal fold change: 1.5). At 4 h after exercise, RNA-seq identified 176 and 156 genes that were differentially expressed in the middle gluteal muscle in hot and cool conditions, respectively. Of these genes, 110 genes were altered in both conditions, whereas 66 genes were only responsive to exercise in the hot condition. Between the two environmental conditions, the expression of only one gene (KANK1) was higher in the hot condition compared with the cool condition. Pathway analysis revealed that the response to temperature stimulus was upregulated only after exercise in the hot condition. Although the overall transcriptional response to exercise was similar in both environmental conditions, our results provide insights into the molecular mechanisms of equine skeletal muscle adaptation to heat acclimation.NEW & NOTEWORTHY Exercise in hot environments raises pulmonary artery temperature to a greater extent than in cool environments in horses. Pathway analysis of RNA-seq revealed expression of genes related to response to temperature stimulus was upregulated only after exercise in a hot environment in equine skeletal muscle.