Physiological genomics最新文献

The accumulation of visceral adipose tissue (VAT) is strongly associated with cardiovascular disease and diabetes. In contrast, individuals with increased subcutaneous adipose tissue (SAT) without corresponding increases in VAT are associated with a metabolic healthy obese phenotype. These observations implicate dysfunctional VAT as a driver of disease processes, warranting investigation into obesity-induced alterations of distinct adipose depots. To determine the effects of obesity on adipose gene expression, male mice (n = 4) were fed a high-fat diet to induce obesity or a normal laboratory diet (lean controls) for 12-14 mo. Mesenteric VAT and inguinal SAT were isolated for bulk RNA sequencing. AT from lean controls served as a reference to obesity-induced changes. The long-term high-fat diet induced the expression of 169 and 814 unique genes in SAT and VAT, respectively. SAT from obese mice exhibited 308 differentially expressed genes (164 upregulated and 144 downregulated). VAT from obese mice exhibited 690 differentially expressed genes (262 genes upregulated and 428 downregulated). KEGG pathway and GO analyses revealed that metabolic pathways were upregulated in SAT versus downregulated in VAT while inflammatory signaling was upregulated in VAT. We next determined common genes that were differentially regulated between SAT and VAT in response to obesity and identified four genes that exhibited this profile: elovl6 and kcnj15 were upregulated in SAT/downregulated in VAT while trdn and hspb7 were downregulated in SAT/upregulated in VAT. We propose that these genes in particular should be further pursued to determine their roles in SAT versus VAT with respect to obesity.NEW & NOTEWORTHY A long-term high-fat diet induced the expression of more than 980 unique genes across subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). The high-fat diet also induced the differential expression of nearly 1,000 AT genes. We identified four genes that were oppositely expressed in SAT versus VAT in response to the high-fat diet and propose that these genes in particular may serve as promising targets aimed at resolving VAT dysfunction in obesity.

Cancer remains a leading cause of death worldwide and although prognosis and survivorship after therapy have improved significantly, current cancer treatments have long-term health consequences. For decades telomerase-mediated telomere maintenance has been an attractive anti-cancer therapeutic target due to its abundance and role in telomere maintenance, pathogenesis, and growth in neoplasms. Telomere maintenance-specific cancer therapies, however, are marred by off-target side effects that must be addressed before they reach clinical practice. Regular exercise training is associated with telomerase-mediated telomere maintenance in normal cells, which is associated with healthy aging. A single bout of endurance exercise training dynamically, but temporarily, increases TERT mRNA and telomerase activity, as well as several molecules that control genomic stability and telomere length (i.e., shelterin and TERRA). Considering the epidemiological findings and accumulating research highlighting that exercise significantly reduces the risk of many types of cancers and the anti-carcinogenic effects of exercise on tumor growth in vitro, investigating the governing molecular mechanisms of telomerase control in context with exercise and cancer may provide important new insights to explain these findings. Specifically, the molecular mechanisms controlling telomerase in both healthy cells and tumors after exercise could reveal novel therapeutic targets for tumor-specific telomere maintenance and offer important evidence that may refine current physical activity and exercise guidelines for all stages of cancer care.

Hypertension affects 1 in 2 U.S. adults and hypertension prevalence increases with aging. Both hypertension and aging can cause arterial remodeling. We investigated the hypothesis that aortic remodeling contributes to age-dependent hypertension in male Sprague Dawley (SD) rats. Compared to young 3-month-old rats 16-month-old male SD rats developed age-dependent hypertension that associated with increased sympathetic tone to the vasculature, elastin disarray and blood pressure variability. Our quantitative proteomic/phosphoproteomic workflow of the aorta identified 2366 proteins and 226 phosphoproteins, from which 58 proteins and 39 phosphoproteins were differentially expressed or phosphorylated respectively between young normotensive controls and aged hypertensive animals. Analysis of the proteome highlighted significant changes in the extracellular matrix, actin cytoskeleton and inflammatory pathways. Analysis of the differential phosphoproteome revealed significant differences in synapse and neuron projection and vascular smooth muscle cell (VSMC) function including actin remodeling and focal adhesions. STRING hypertension network analysis identified 13 differentially expressed and 10 differentially phosphorylated proteins associated with hypertension. Within the STRING analysis we observed 2 major areas of correlation of alterations in the aorta proteome with increased hypertension risk score - vascular inflammation and VSMC function. The majority of the identified phosphorylation sites (78.57%) in hypertension-relevant hyperphosphorylated proteins were located at serine residues. Collectively, we report that arterial remodeling in age-dependent hypertension is associated with an altered extracellular matrix and actin cytoskeleton and modulation of VSMC focal adhesion networks and neuron/synapse interactions.

Intratumoral microbiota and host genes interact to promote gastrointestinal disorders, but how the two interact to influence host tumorigenesis remains unclear. Here, we utilized a machine learning-based framework to jointly dissect the paired intratumoral microbiome and host transcriptome profiles in patients with colon adenocarcinoma, hepatocellular carcinoma, and gastric cancer. We identified associations between intratumoral microbes and host genes that depict shared as well as cancer type-specific patterns. We found that a common set of host genes and pathways implicated in cell proliferation and energy metabolism are associated with cancer type-specific intratumoral microbes. In addition, we also found that intratumoral microbes that have been implicated in three gastrointestinal tumors, such as Lachnoclostridium, are correlated with different host pathways in each tumor, indicating that similar microbes can influence host tumorigenesis in a cancer type-specific manner by regulation of different host genes. Our study reveals patterns of association between intratumoral microbiota and host genes in gastrointestinal tumors, providing new insights into the biology of gastrointestinal tumors.NEW & NOTEWORTHY Our study constitutes a pivotal advancement in elucidating the intricate relationship between the intratumoral microbiome and host gene regulation, thereby gaining insights into the pivotal role that the intratumoral microbiome plays in the etiology of gastrointestinal tumors.

The extracellular isoform of superoxide dismutase (SOD3) is decreased in patients and animals with pulmonary hypertension (PH). The human R213G single-nucleotide polymorphism (SNP) in SOD3 causes its release from tissue extracellular matrix (ECM) into extracellular fluids, without modulating enzyme activity, increasing cardiovascular disease risk in humans and exacerbating chronic hypoxic PH in mice. Given the importance of interstitial macrophages (IMs) to PH pathogenesis, this study aimed to determine whether R213G SOD3 increases IM accumulation and alters IM reprogramming in response to hypoxia. R213G mice and wild-type (WT) controls were exposed to hypobaric hypoxia for 4 or 14 days compared with normoxia. Flow cytometry demonstrated a transient increase in IMs at day 4 in both strains. Contrary to our hypothesis, the R213G SNP did not augment IM accumulation. To determine strain differences in the IM reprogramming response to hypoxia, we performed RNAsequencing on IMs isolated at each timepoint. We found that IMs from R213G mice exposed to hypoxia activated ECM-related pathways and a combination of alternative macrophage and proinflammatory signaling. Furthermore, when compared with WT responses, IMs from R213G mice lacked metabolic remodeling and demonstrated a blunted anti-inflammatory response between the early (day 4) and later (day 14) timepoints. We confirmed metabolic responses using Agilent Seahorse assays, whereby WT, but not R213G, IMs upregulated glycolysis at day 4 that returned to baseline at day 14. Finally, we identify differential regulation of several redox-sensitive upstream regulators that could be investigated in future studies.NEW & NOTEWORTHY Redistributed expression of SOD3 out of tissue ECM due to the human R213G SNP exacerbates chronic hypoxic PH. Highlighting the importance of macrophage phenotype, our findings reveal that the R213G SNP does not exacerbate pulmonary macrophage accumulation in response to hypoxia but influences their metabolic and phenotypic reprogramming. We demonstrate a deficiency in the metabolic response to hypoxic stress in R213G macrophages, associated with weakened inflammatory resolution and activation of profibrotic pathways implicated in PH.

Identifying associations between phenotype and genotype is the fundamental basis of genetic analyses. Inspired by frequentist probability and the work of R. A. Fisher, genome-wide association studies (GWAS) extract information using averages and variances from genotype-phenotype datasets. Averages and variances are legitimated upon creating distribution density functions obtained through the grouping of data into categories. However, as data from within a given category cannot be differentiated, the investigative power of such methodologies is limited. Genomic informational field theory (GIFT) is a method specifically designed to circumvent this issue. The way GIFT proceeds is opposite to that of GWAS. Although GWAS determines the extent to which genes are involved in phenotype formation (bottom-up approach), GIFT determines the degree to which the phenotype can select microstates (genes) for its subsistence (top-down approach). Doing so requires dealing with new genetic concepts, a.k.a. genetic paths, upon which significance levels for genotype-phenotype associations can be determined. By using different datasets obtained in Ovis aries related to bone growth (dataset 1) and to a series of linked metabolic and epigenetic pathways (dataset 2), we demonstrate that removing the informational barrier linked to categories enhances the investigative and discriminative powers of GIFT, namely that GIFT extracts more information than GWAS. We conclude by suggesting that GIFT is an adequate tool to study how phenotypic plasticity and genetic assimilation are linked.NEW & NOTEWORTHY The genetic basis of complex traits remains challenging to investigate using classic genome-wide association studies (GWASs). Given the success of gene editing technologies, this point needs to be addressed urgently since there can only be useful editing technologies whether precise genotype-phenotype mapping information is available initially. Genomic informational field theory (GIFT) is a new mapping method designed to increase the investigative power of biological/medical datasets suggesting, in turn, the need to rethink the conceptual bases of quantitative genetics.

Stenothermal Antarctic notothenioid fishes are noteworthy for their history of isolation in extreme cold and their corresponding lack of the canonical heat shock response. Despite extensive transcriptomic studies, the mechanistic basis for stenothermy has not been fully elucidated. Given that the proteome better represents an organism's physiology, the possibility exists that some aspects of stenothermy arise posttranscriptionally. Here, Antarctic emerald rockcod (Trematomus bernacchii) were sampled after exposure to chronic and/or acute high temperatures, followed by a thorough assessment of proteomic responses in the brain, gill, and kidney. Few cellular stress response proteins were induced, and overall responses were modest in terms of the numbers of differentially expressed proteins and their fold changes. Inconsistencies in protein induction across treatments and tissues are suggestive of dysregulation, rather than an adaptive response. Changes in regulation of the translational machinery in Antarctic notothenioids could explain these patterns. Some components of translational regulatory pathways are highly conserved [e.g., Ser-52, eukaryotic translation initiation factor 2α (eIF2α)], but other proteins comprising the cellular "integrated stress response," specifically, the eIF2α kinases general control nonderepressible 2 (GCN2) and PKR-like endoplasmic reticulum kinase (PERK), may have evolved along different trajectories in Antarctic fishes. Taken together, these observations suggest a novel hypothesis for stenothermy and the absence of a coordinated cellular stress response in Antarctic fishes.NEW & NOTEWORTHY Antarctic fishes have some of the lowest known heat tolerances among vertebrates, but the molecular mechanisms underlying this pattern are not fully understood. By combining detailed analyses of protein expression patterns in several tissues under various heat treatments with a broader evolutionary perspective, this study offers a novel hypothesis to explain the narrow range of temperature tolerance in this extraordinary group of fishes.

The growth of the ovarian antral follicle is a complex process that is difficult to study, especially in human and nonhuman primates. Understanding the antral stage of development is key to new approaches to regulating reproduction. This study analyzed cohorts of three sizes of developing antral follicles obtained from adult rhesus macaque females using RNA sequencing of oocytes and cumulus and granulosa cells. The overall objective of this study was to identify key developmental changes in gene expression in oocytes, granulosa, and cumulus cells, as nonhuman primate antral stage follicles transition through progressively larger sizes in the absence of exogenous hormonal stimulation. Only a relatively small number of genes displayed altered mRNA expression levels in any of the three cell types during this period. Most of the identified differentially expressed genes (DEGs) decreased in the granulosa cells or increased in the cumulus cells. Although the number of DEGs observed was small, these DEGs indicate predicted effects on distinct upstream regulators in the cumulus and granulosa cells. This study is particularly important because it shows for the first time the gene expression changes during antral follicle growth in a medically relevant model.NEW & NOTEWORTHY Changes in gene expression in oocytes, granulosa, and cumulus cells were determined in nonhuman primate antral stage ovarian follicles transitioning through progressively larger sizes without exogenous hormonal stimulation. Only a small number of genes displayed altered mRNA expression levels in any of the three cell types. Most of the differentially expressed genes (DEGs) decreased in granulosa cells or increased in cumulus cells. These results identified upstream regulators of antral follicle development.

The severity of respiratory syncytial virus (RSV) may be linked to host genetic susceptibility. Surfactant protein (SP) genetic variants have been associated with RSV severity, but the impact of single-nucleotide polymorphism (SNP)-SNP interactions remains unexplored. Therefore, we used a novel statistical model to investigate the association of SNP-SNP interactions of SFTP genes with RSV severity in two- and three-interaction models. We analyzed available genotype and clinical data from prospectively enrolled 405 children diagnosed with RSV, categorizing them into moderate or severe RSV groups. Using Wang's statistical model, we studied significant associations of SNP-SNP interactions with RSV severity in a case-control design. We observed, first, association of three interactions with increased risk of severe RSV in a two-SNP model. One intragenic interaction was between SNPs of SFTPA2, and the other two were intergenic, involving SNPs of hydrophilic and hydrophobic SPs alone. We also observed, second, association of 22 interactions with RSV severity in a three-SNP model. Among these, 20 were unique, with 12 and 10 interactions associated with increased or decreased risk of RSV severity, respectively, and included at least one SNP of either SFTPA1 or SFTPA2. All interactions were intergenic except one, among SNPs of SFTPA1. The remaining interactions were either among SNPs of hydrophilic SPs alone (n = 8) or among SNPs of both hydrophilic or hydrophobic SPs (n = 11). Our findings indicate that SNPs of all SFTPs may contribute to genetic susceptibility to RSV severity. However, the predominant involvement of SFTPA1 and/or SFTPA2 SNPs in these interactions underscores their significance in RSV severity.NEW & NOTEWORTHY Although surfactant protein (SP) genetic variants are associated with respiratory syncytial virus (RSV) severity, the impact of single-nucleotide polymorphism (SNP)-SNP interactions of SP genes remained unexplored. Using advanced statistical models, we uncovered 22 SNP-SNP interactions associated with RSV severity, with notable involvement of SFTPA1 and SFTPA2 SNPs. This highlights the comprehensive role of all SPs in genetic susceptibility to RSV severity, shedding light on potential avenues for targeted interventions.

Marine fishes excrete excess H⁺ using basolateral Na⁺-K⁺-ATPase (NKA) and apical Na⁺/H⁺ exchanger 3 (NHE3) in gill ionocytes. However, the mechanisms that regulate H⁺ excretion during exposure to environmentally relevant hypercapnia (ERH) remain poorly understood. Here, we explored transcriptomic, proteomic, and cellular responses in gills of juvenile splitnose rockfish (Sebastes diploproa) exposed to 3 days of ERH conditions (pH ∼7.5, ∼1,600 μatm Pco₂). Blood pH was fully regulated at ∼7.75 despite a lack of significant changes in gill 1) mRNAs coding for proteins involved in blood acid-base regulation, 2) total NKA and NHE3 protein abundance, and 3) ionocyte density. However, ERH-exposed rockfish demonstrated increased NKA and NHE3 abundance on the ionocyte plasma membrane coupled with wider apical membranes and greater extension of apical microvilli. The observed gill ionocyte remodeling is consistent with enhanced H⁺ excretion that maintains blood pH homeostasis during exposure to ERH and does not necessitate changes at the expression or translation levels. These mechanisms of phenotypic plasticity may allow fishes to regulate blood pH during environmentally relevant acid-base challenges and thus have important implications for both understanding how organisms respond to climate change and for selecting appropriate metrics to evaluate its impact on marine ecosystems.NEW & NOTEWORTHY Splitnose rockfish exposed to environmentally relevant hypercapnia utilize existing proteins (rather than generate additional machinery) to maintain homeostasis.