Physiological genomics最新文献

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.

Risk factors for cardiac arrhythmias that can cause sudden death and heart failure include genetics, age, lifestyle, and other environmental factors. The study assessed electrocardiography (ECG) traits in BXD mice and explored associated quantitative trait loci (QTLs). Five-minute electrocardiograms were recorded in 44 BXD strains at 4-5 mo of age (n ≥ 5 mice/sex/strain). ECG and arrhythmia traits were associated with echocardiography, blood pressure, genome, and heart transcriptome data followed by expression QTL mapping. A significant variability in ECG parameters and arrhythmias was recorded among BXDs. Among male BXDs, QRS duration was significantly associated with increased left ventricular internal diameter (LVID) and reduced ejection fraction and fractional shortening, whereas premature ventricular contractions (PVCs) were correlated with LVID, left ventricular (LV) volumes, and pulmonary vein peak pressure. In female BXDs, PVCs and premature atrial contractions (PACs) were significantly related with right ventricular ID and cardiac output. One significant QTL associated with QTc and JT durations was identified on Chromosome (Chr) 3 in male BXDs, whereas Chr 9 locus was suggestive for association with QTc and QT intervals in female mice. Gon4l was predicted as a strong candidate gene associated with repolarization abnormalities including short or long QT syndromes in humans. Study results suggested an influence of genetic background on expression of ECG parameters and arrhythmias based on significant variations of those traits between mouse strains of the BXD family. We conclude that murine BXD family can serve as a valuable reference for systems biology and comparative predictions of arrhythmia disorders.NEW & NOTEWORTHY Our study identified significant variances in ECG phenotypes and arrhythmias segregation in BXD mice. A significant quantitative trait locus (QTL) on Chromosome (Chr) 3 in the mouse genome was associated with increased QTc and JT intervals in male BXD mice. A suggestive QTL on Chr 9 associated with QT and QTc intervals was determined in female BXD mice. We identified a strong candidate gene, Gon4l, that may underlie cardiac repolarization abnormalities such as long and short QT syndromes.

Risk of cardiovascular disease (CVD) in women increases with the menopausal transition. Using a chemical model (4-vinylcyclohexene diepoxide; VCD) of accelerated ovarian failure, we previously demonstrated that menopausal females are more susceptible to CVD compared with peri- or premenopausal females like humans. Yet, the cellular and molecular mechanisms underlying this shift in CVD susceptibility across the pre- to peri- to menopause continuum remain understudied. In this work using the VCD mouse model, we phenotyped cellular and molecular signatures from hearts at each hormonally distinct stage that included transcriptomic, proteomic, and cell biological analyses. The transcriptional profile of premenopausal hearts clustered separately from perimenopausal and menopausal hearts, which clustered more similarly. Proteomics also revealed hormonal clustering; perimenopausal hearts grouped more closely with premenopausal than menopausal hearts. Both proteomes and transcriptomes showed similar trends in genes associated with atherothrombosis, contractility, and impaired nuclear signaling between pre-, peri-, and menopausal murine hearts. Further analysis of posttranslational modifications (PTMs) showed hormone-dependent shifts in the phosphoproteome and acetylome. To further interrogate these findings, we triggered pathological remodeling using angiotensin II (Ang II). Phosphorylation of AMP-activated protein kinase (AMPK) signaling and histone deacetylase (HDAC) activity were found to be dependent on hormonal status and Ang II stimulation. Finally, knockdown of anti-inflammatory regulatory T cells (Treg) exacerbated Ang II-dependent fibrosis implicating HDAC-mediated epigenetic suppression of Treg activity. Taken together, we demonstrated unique cellular and molecular profiles underlying the cardiac phenotype of pre-, peri-, and menopausal mice supporting the necessity to study CVD in females across the hormonal transition.NEW & NOTEWORTHY Cycling and perimenopausal females are protected from cardiovascular disease (CVD) whereas menopausal females are more susceptible to CVD and other pathological sequalae. The cellular and molecular mechanisms underlying loss of CVD protection across the pre- to peri- to menopause transition remain understudied. Using the murine 4-vinylcyclohexene diepoxide (VCD) model of menopause we highlight cellular and molecular signatures from hearts at each hormonally distinct stage that included transcriptomic, proteomic, and cell biological analyses.