Physiological genomics最新文献

The menopausal transition is associated with an increased risk of obesity, which can be ameliorated by hormone replacement therapy. However, the independent and interactive effects of obesity and menopause on the gut microbiota, along with the influence of hormone therapy, remain poorly understood. To address this, this study used a mouse model using sham-operated and ovariectomized mice, with or without high-fat diet-induced obesity, to disentangle the roles of menopause and obesity. Ovariectomized mice on a high-fat diet were further treated with estradiol to assess the regulatory effects of hormone supplementation on the gut microbiota. The results showed that obesity and ovariectomy altered the relative abundances of 29 and 7 genera, and 243 and 99 amplicon sequence variants, respectively, indicating a stronger impact of obesity on gut microbial composition. Notably, ovariectomy increased the abundance of Faecalibaculum and enriched microbial taxa capable of producing estrogen-metabolizing enzymes, including Bifidobacterium and Dubosiella species, as well as the predicted abundance of the estrobolome enzyme β-glucuronidase. Estradiol supplementation increased the relative abundance of Bacteroides and decreased Akkermansia, both of which possess distinct β-glucuronidase subtypes. It also reduced the species Faecalibaculum rodentium, that positively associated with adiposity. Together, these findings highlight the distinct and significant impacts of obesity and menopause on the gut microbiota and suggest that estrogen supplementation modulates microbial features linked to metabolic health. These results further implicate the potential of modulating the gut microbiota to improve postmenopausal health outcomes.NEW & NOTEWORTHY This study investigates how obesity, menopause, and estrogen supplementation influence the gut microbiota. The findings highlight the distinct and significant effects of obesity and menopause in shaping microbial composition and suggest that estrogen supplementation modulates microbial features associated with metabolic health.

The initiating cellular events in cystic fibrosis (CF) hepatobiliary disease are not well characterized, in part due to the lack of accessibility of primary tissues. However, enhanced longevity due to highly effective modulator therapies has generated renewed interest in the key aspects of liver and gallbladder disease, and how these might be treated in people with cystic fibrosis (pwCF). To extend the CF hepatobiliary knowledge base, we performed a transcriptomic analysis of liver and gallbladder development in the wild-type (WT) and CFTR^-/- sheep. Bulk RNA was extracted from each tissue at specific timepoints through gestation (from 50 days to term) and used for RNA sequencing (RNA-seq). Differentially expressed genes between the timepoints within each genotype and between WT and CFTR^-/- sheep at each timepoint were identified and then used in gene ontology process enrichment analysis to reveal altered biological processes. We find that at the molecular level, the gallbladder in the CFTR^-/- animals is both structurally and functionally compromised by midgestation, consistent with the observed microgallbladder phenotype. In the liver, many aspects of differentiation are apparently well-established early in gestation. However, we find functional immaturity in the CFTR^-/- liver at term, where genes associated with many key metabolic processes do not show the upregulation seen at term in the WT liver. We also show that the regulatory mechanisms for the CFTR gene in ovine gallbladder cells are highly conserved with those elucidated at the human CFTR locus, further enhancing the relevance of these data to advance understanding of hepatobiliary disease in pwCF.NEW & NOTEWORTHY We use a physiological genomics approach to further understand the etiology of cystic fibrosis gallbladder and liver disease by using a large animal (sheep) model of organ development. We find that the gallbladder in the CFTR^-/- animals is both structurally and functionally compromised by midgestation. We also observe functional immaturity in the CFTR^-/- liver at term, where genes associated with many key metabolic processes do not show the upregulation seen at term in wild-type liver.

Periodontal therapy leverages intercellular and intertissue interactions between epithelium and stroma, which mediate healing and regeneration. Importantly, grafting stroma from different regions elicits different healing responses: transplantation of gingival stroma can convert alveolar mucosa into keratinized gingiva, and vice versa. This striking clinical observation suggests that the stromal tissues of oral mucosa and gingiva provide distinct instructional signals. Our aims were to investigate the molecular differences between mucosa and gingiva and the impact of periodontal infection on intertissue interactions. We used human single-cell RNA-sequencing (RNA-seq) data to compare gene expression patterns and intercellular interactions of: 1) adult oral mucosa and gingiva and 2) healthy gingiva and periodontitis-affected gingiva. Altered gene expression in junctional epithelial cells in periodontitis included not only inflammatory but also antioxidant genes, reflecting the potential of oral tissues to maintain health and resist bacterial infection. Many ligand/receptor genes were also enriched in junctional epithelium, highlighting intercellular interactions. Oral mucosal and gingival stroma expressed distinct genes related to signaling and extracellular matrix associated with their tissue phenotypes: for example, collagens and secreted protein acidic and cysteine-rich (SPARC) in the gingiva, and elasticity-related coagulation factor XIII A chain (F13A1) in the mucosa. Ligand-receptor analyses predicted endothelial cells and fibroblasts as the primary senders of signaling ligands. Notably, autocrine signaling was predicted to be prevalent within periodontitis-affected fibroblasts, suggesting potential autofeedback regulation in periodontitis. We present unbiased single-cell molecular characterizations of human oral tissues in health and periodontitis. These findings lay the groundwork for future research into periodontal therapies.NEW & NOTEWORTHY To explore differences between oral mucosa and gingiva in health and disease, we analyzed human single-cell RNA-sequencing data. In periodontitis, altered gene expression in junctional epithelium included not only inflammatory but also antioxidant genes, reflecting the potential of oral tissues to resist bacterial infection. Each cell type-fibroblasts, endothelial, and immune cells-expressed genes that distinguished mucosa from gingiva, as well as healthy from diseased gingiva. These findings provide insights into periodontitis and periodontal therapy.

Physiological Genomics (PG) published its first issue in July 1999, with the goal of providing a forum for scientists to exchange ideas and scientific results related to the linkage between genetic information and physiological function. In this review, past and present editors reflect on PG's role in the scientific community, the founding of the journal and the historical context in which it was formed within the American Physiological Society (APS). The editors reflect on a critical conference that united physiologists and geneticists and their determination for APS to take the lead in integrating these communities. In the past 25 years, key technologies for linking genes to physiology including methods for DNA sequencing, connecting genotype with phenotype, and monitoring gene expression, metabolites, and microbiota have all been revolutionized, creating a dynamic scientific environment that has resulted in highly impactful research across a wide range of fields. As methods, technologies, and data analysis tools have developed, PG has been a consistent forum for sharing cutting-edge research on the latest advances in the rapidly evolving field of linking molecular data to physiological function. This article highlights the key technological advances related to the connection between genes and physiology. The contribution of the journal to the scientific community during the time periods of each of the five Editors-in-Chief are summarized, illuminating key technological approaches featured in PG and scientific questions that were addressed. The article ends with a look forward, describing what the authors anticipate for the future of PG.

Seasonal life-history events, such as migration, hibernation, and reproduction, depend on coordinated physiological changes. In vertebrates, a conserved thyroid hormone-signaling pathway in the hypothalamus is known to trigger many of these seasonal transitions. However, the broader processes and regulators modulating seasonal physiology are poorly defined. Recent research in Arctic ground squirrels (AGS, Urocitellus parryii) revealed that hypothalamic thyroid hormone signaling is activated, and markers of tanycytic remodeling are expressed in late hibernation in anticipation of springtime reproduction. We conducted RNA-sequencing on hypothalamic micropunches encompassing the arcuate nucleus, median eminence, pars tuberalis, and third ventricle in male and female AGS at early and late hibernation. We found substantial sex differences in the hypothalamic transcriptome across hibernation. Functional enrichment analysis of gene expression data revealed an upregulation of processes and pathways related to hormone transport and neurogenesis in females, whereas this was less apparent in males. Transcription factor binding site analysis of differentially expressed genes identified upstream regulators involved in glial cell differentiation, neuronal development, survival, and plasticity. Notably, many of the intersecting genes from these analyses were localized to specialized glial cells (tanycytes) lining the floor and walls of the third ventricle. Our findings support a model in which annual changes in gene expression rely on a progressive remodeling of tanycytes across hibernation. This remodeling may contribute to seasonal changes in neuronal plasticity and function of the hypothalamus, priming the brain in anticipation of shifting physiological demands upon hibernation termination.NEW & NOTEWORTHY We examine how the transcriptome of hypothalamic micropunches changes across the hibernation season. Our analyses uncover sex-specific changes to regulatory processes associated with hormone transport and neurogenesis. Genes linked to these processes and regulators are strongly localized to third ventricle tanycytes, consistent with the key role these cells play in regulating seasonal physiological changes. Our study supports that using sex as a biological variable is essential for understanding the mechanisms underlying seasonal life-history transitions.

Extracellular vesicles (EVs) are small, membrane-bound vesicles that transfer biological content through the extracellular environment. The role of EVs in energy metabolism has primarily focused on EV proteins and microRNAs, with less attention on the metabolic content of EVs. This exploratory study assessed changes in the EV metabolome in response to an arduous, 16-day military training exercise. Forty male soldiers (21 ± 2 yr, 24.8 ± 2.7 kg/m²) provided blood from which circulating EVs were isolated and completed assessments of body composition and lower body power on days 1 (PRE) and 16 (POST) of a mountain training exercise (MTX). Total daily energy expenditure during the MTX was 4,187 ± 519 kcal·day^-1. Fat mass (POST-PRE [95% confidence interval]: -0.9 [-1.3, -0.6] kg), lean body mass (-1.6 [-2.0, -1.2] kg), body fat percentage (-0.7 [-1.1, -0.3]%), and lower body power (-133 [-204, -63] W) decreased from PRE to POST (P < 0.05). Global metabolite profiling identified 81 metabolites from lipid (81%), energy (5%), cofactor and vitamin (5%), xenobiotic (4%), carbohydrate (2%), amino acid (1%), and nucleotide (1%) pathways in serum-derived EVs. After adjusting for EV concentration, 11 metabolites were different from PRE to POST (P < 0.05, Q < 0.20), with the largest increases in the oxidative stress-associated metabolites 5-oxoproline and benzoate. Changes in lean body mass were positively associated with changes in the energy metabolites citrate (ρ = 0.361, P = 0.022) and phosphate (ρ = 0.369, P = 0.019). Findings suggest that EV metabolites change in response to physiological stress and reflect increased oxidative stress, energy metabolism, and fatty acid metabolism, which may provide early indicators of stress adaptations relevant for optimizing training and sustaining military performance.NEW & NOTEWORTHY EV metabolites change in response to periods of increased metabolic demand, reflecting increased oxidative stress, energy metabolism, and fatty acid metabolism, and may be associated with changes in lean body mass. This exploratory study adds to the limited existing literature by highlighting the potential of EV-derived metabolites to provide insight into metabolic responses and their contribution to stress-induced metabolic adaptations.

Preeclampsia is a multifaceted pregnancy-associated hypertensive disorder that poses a major threat to maternal and fetal health. Though the etiology is not fully understood, syncytiotrophoblast stress is postulated to be a major driver of maternal symptomology. We previously demonstrated that regulator of G protein signaling-2 (RGS2) expression decreases in human preeclamptic placenta and has a transcriptional dependence on histone deacetylase 9 (HDAC9) in trophoblast cells. Furthermore, experimental reductions of Rgs2 expression in the mouse fetoplacental unit are sufficient to induce preeclampsia-like features, including placental stress, in C57BL/6J dams. Here, we examined the hypotheses that HDAC9 and RGS2 are both expressed within syncytiotrophoblasts, that HDAC9 and RGS2 expression are positively correlated within these cells, and that expression of each is reduced within syncytiotrophoblasts during preeclampsia. HDAC9 and RGS2 mRNA were localized and quantified in syncytiotrophoblast cells of human placental samples from pregnancies with and without preeclampsia, using laser-capture microdissection and in situ hybridization methods. Expression of Hdac9 and Rgs2 was similarly localized in the syncytiotrophoblast of the mouse placenta. Throughout, HDAC9/Hdac9 and RGS2/Rgs2 were detected and positively correlated in syncytiotrophoblasts, but expression of each was substantially reduced during preeclampsia. These results document reduced HDAC9 and RGS2 expression specifically in syncytiotrophoblast cells during preeclampsia and provide additional correlative support of HDAC9-mediated control of RGS2 expression within this population of trophoblasts. This work provides rationale to further explore cell-specific disruptions in HDAC9 and RGS2 control and function as a cause of syncytiotrophoblast stress and ultimately preeclampsia.NEW & NOTEWORTHY Syncytiotrophoblast stress contributes to the pathogenesis of preeclampsia, but many of the underlying causes remain undetermined. Previous work has implicated the loss of placental HDAC9-mediated Rgs2 transcription in the disorder. Extending these findings, we report that HDAC9 and RGS2 were abundant and localized primarily to syncytiotrophoblast cells of the control placenta. Expression of both targets was attenuated in these cells during preeclampsia and thus may be an underappreciated source of syncytiotrophoblast stress, warranting further investigation.

The human microbiome is emerging as a key regulator of cancer biology, modulating tumor development, immune dynamics, and therapeutic responses across diverse malignancies. In this review, recent insights are synthesized regarding how microbial communities (bacterial, fungal, and viral) shape oncogenic signaling, immune checkpoint blockade (ICB) efficacy, and metabolic reprogramming in lung, pancreatic, colorectal, breast, cervical, melanoma, and gastric cancers. Mechanistic links between microbial metabolites, intratumoral colonization, and host immune phenotypes are highlighted proposing that the microbiome constitutes a programmable axis within the tumor immune-metabolic ecosystem. Drawing on multiomics integration and translational studies, a shift from associative profiling toward causal, spatially resolved, and intervention-ready frameworks is proposed. This perspective positions the microbiome not as a passive bystander, but as a coevolving participant in tumor progression and treatment response, with the potential to reshape diagnostics, prognostics, and therapeutic strategies in precision oncology.