Physiological genomics最新文献

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.

Sleep is an essential, tightly regulated biological function. Sleep is also a homeostatic process, with the need to sleep increasing as a function of being awake. Acute sleep deprivation (SD) increases sleep need, and subsequent recovery sleep (RS) discharges it. SD is known to alter brain gene expression in rodents, but it remains unclear which changes are linked to sleep homeostasis. To investigate this question, we analyzed RNA-seq data from adult male mice subjected to 3 and 5-6 h of SD and 2 and 6 h of subsequent RS. We hypothesized that molecular changes associated with sleep homeostasis would mirror sleep pressure dynamics as defined by brain electrical activity, peaking at 5-6 h of SD and no longer differentially expressed after 2 h of RS. We report that 5-6 h of SD produces the largest effect on gene expression, and the majority of differentially expressed genes normalize after 2 h of RS. These genes are involved in cellular redox homeostasis, DNA damage/repair, and chromatin regulation and may underlie the molecular basis of sleep homeostasis. Genes associated with cellular stress do not normalize within 6 h of RS and may underlie non-sleep-specific effects of SD. In addition, RS affects gene expression related to energy metabolism and Wnt-signaling, potentially contributing to its restorative effects. Finally, our study also points to the regulation of expression of a subset of circadian transcription factors as a function of sleep need. Overall, our results offer novel insights into the molecular mechanisms underlying sleep homeostasis and the broader effects of SD.NEW & NOTEWORTHY This study investigates different time points of sleep deprivation and recovery sleep to better understand the molecular processes influenced by sleep and lack of sleep. This study highlights redox metabolism, chromatin regulation, and DNA damage/repair as molecular mechanisms linked to sleep homeostasis while showing the effects of stress are probably non-sleep-specific based on transcriptional dynamics.

Neuromuscular electrical stimulation (NMES) can potentially be used to prevent venous thromboembolism; however, its impact on coagulation-related factors remains poorly understood. We aimed to investigate the acute effects on coagulation- and cardiovascular factors immediately after a 2-h NMES session. Levels of overall hemostatic potential (OHP), fibrinogen, factor VIII, and Olink proteomic cardiovascular factors were assessed before and after the NMES session in 36 healthy participants (20 males and 16 females) with a mean age of 31.9 yr. NMES was administered using integrated textile electrodes in pants (NMES pants). Mean intensities during the quadriceps, hamstrings, and gluteus muscle stimulation were 16.5, 20.5, and 25.4 mA, respectively, corresponding to submaximal intensity levels with acceptable discomfort (just below 4 on the visual analogue scale [VAS], 0-10). The NMES session resulted in a significant increase in mean (SD) OHP [94.4 (28.3) to 103 (31.0)], and overall coagulation potential [292 (50.4) to 307(49.8)], and a decrease in overall fibrinolytic potential [68.2 (5.46) to 67.1 (5.20)]. These changes were highly correlated with the increase in fibrinogen (all R > 0.7, P ≤ 0.001), but not with the increase in factor VIII. In addition, 18 of 92 cardiovascular proteins, specifically those involved in regulating inflammation and extracellular matrix remodeling, were influenced by NMES; however, low correlations were found between the changes in these proteins and OHP analyses. In conclusion, the NMES session resulted in a slight increase in the coagulative state, mirroring that seen after a bout of regular exercise. The changes observed in cardiovascular factors, which are mostly not directly related to coagulation, suggest that NMES may subsequently modulate inflammatory responses, warranting further investigation.NEW & NOTEWORTHY The immediate response to a 2-h neuromuscular electrical stimulation (NMES) session, delivered at an acceptable level of discomfort using NMES-pants, marginally increases the coagulative state, similar to what is observed after regular physical exercise. This change is not expected to significantly increase the risk of blood clotting, as all factors remain within the normal reference range. Interestingly, NMES simultaneously appears to affect proteins that regulate the transition of inflammation into an anti-inflammatory response.