Egl-9 Family Hypoxia Inducible Factor Research Articles

High expression levels of haem oxygenase-1 promote ferroptosis in macrophage-derived foam cells and exacerbate plaque instability

Plaque rupture with consequent thrombosis is the leading cause of acute cardiovascular events, during which macrophage death is a hallmark. Ferroptosis is a pivotal intermediate link between early and advanced atherosclerosis. Existing evidence indicates the involvement of macrophage ferroptosis in plaque vulnerability; however, the exact mechanism remains elusive. The aim of this study was to explore key ferroptosis-related genes (FRGs) involved in plaque progression and the underlying molecular mechanisms involved. The expression landscape of FRGs was obtained from atherosclerosis-related GEO datasets. Molecular mechanism studies of ferroptosis were performed using bone marrow-derived macrophages (BMDMs) and macrophage-derived foam cells (MDFCs). Bioinformatics analysis and immunohistochemistry revealed that macrophage haem oxygenase-1 (HMOX1) is the key FRG involved in plaque destabilization. Hypoxic conditions induced a significant increase in Hmox1 expression in MDFCs but not in macrophages. In addition, the beneficial or deleterious effects of Hmox1 were dependent on the degree of Hmox1 induction. Hmox1 overexpression drove inflammatory responses and ferroptotic oxidative stress in MDFCs and aggravated the plaque burden in atherosclerotic model mice. Further mechanistic investigations demonstrated that hypoxia-mediated degradation of egl-9 family hypoxia-inducible factor 3 (Egln3) stabilized Hif1a, which subsequently promoted Hmox1 transcription. Our findings suggest that high Hmox1 expression under hypoxia is deleterious to MDFC viability and plaque stability, providing a reference for the management of acute cardiovascular events.

A Free Amino Acid Diet Alleviates Colorectal Tumorigenesis through Modulating Gut Microbiota and Metabolites.

Colorectal cancer (CRC), a major global health concern, may be influenced by dietary protein digestibility impacting gut microbiota and metabolites, which is crucial for cancer therapy effectiveness. This study explored the effects of a casein protein diet (CTL) versus a free amino acid (FAA)-based diet on CRC progression, gut microbiota, and metabolites using carcinogen-induced (AOM/DSS) and spontaneous genetically induced (ApcMin/+ mice) CRC mouse models. Comprehensive approaches including 16s rRNA gene sequencing, transcriptomics, metabolomics, and immunohistochemistry were utilized. We found that the FAA significantly attenuated CRC progression, evidenced by reduced colonic shortening and histopathological alterations compared to the CTL diet. Notably, the FAA enriched beneficial gut bacteria like Akkermansia and Bacteroides and reversed CRC-associated dysbiosis. Metabolomic analysis highlighted an increase in ornithine cycle metabolites and specific fatty acids, such as Docosapentaenoic acid (DPA), in FAA-fed mice. Transcriptomic analysis revealed that FAA up-regulated Egl-9 family hypoxia inducible factor 3 (Egln 3) and downregulated several cancer-associated pathways including Hippo, mTOR, and Wnt signaling. Additionally, DPA was found to significantly induce EGLN 3 expression in CRC cell lines. These results suggest that FAA modulate gut microbial composition, enhance protective metabolites, improve gut barrier functions, and inhibit carcinogenic pathways.

Leukocytes and Endothelial Cells Participate in the Pathogenesis of Alzheimer's Disease: Identifying New Biomarkers Mirroring Metabolic Alterations.

Alzheimer's disease (AD) is a neurodegenerative disorder marked by amyloid-β accumulation, tau dysfunction, and neuroinflammation, involving endothelial cells and leukocytes. The breakdown of the blood-brain barrier allows immune cell infiltration, intensifying inflammation. A decreased ratio of Connexin-37 (Cx37, also known as GJA4: Gap Junction Protein Alpha 4) and Prolyl Hydroxylase Domain-Containing Protein 3 (PHD3, also known as EGLN3: Egl-9 Family Hypoxia Inducible Factor 3), Cx37/PHD3, consistently observed in different AD-related models, may represent a novel potential biomarker of AD, albeit the exact mechanisms underlying this phenomenon, most likely based on gap junction-mediated cellular interaction that modulate the cellular metabolite status, remain to be fully elucidated.

EGLN3 attenuates gastric cancer cell malignant characteristics by inhibiting JMJD8/NF-κB signalling activation independent of hydroxylase activity.

The expression of Egl-9 family hypoxia-inducible factor 3 (EGLN3) is notably decreased in various malignancies, including gastric cancer (GC). While the predominant focus has been on the hydroxylase activity of EGLN3 for its antitumour effects, recent findings have suggested nonenzymatic roles for EGLN3. This study assessed the clinical significance of EGLN3 expression in GC and explored the connection between EGLN3 DNA promoter methylation and transcriptional silencing. To investigate the effect of EGLN3 on GC cells, a gain-of-function strategy was adopted. RNA sequencing was conducted to identify the key effector molecules and signalling pathways associated with EGLN3. EGLN3 expression was significantly reduced in GC tissues, correlating with poorer patient prognosis. EGLN3 hypermethylation disrupts transcriptional equilibrium, contributing to deeper tumour invasion and lymph node metastasis, thus exacerbating GC progression. Conversely, restoration of EGLN3 expression in GC cells substantially inhibited cell proliferation and metastasis. EGLN3 was also found to impede the malignant progression of GC cells by downregulating Jumonji C domain-containing protein 8-mediated activation of the NF-κB pathway, independent of its hydroxylase activity. EGLN3 has the potential to hinder the spread of GC cells through a nonenzymatic mechanism, thereby shedding light on the complex nature of GC progression.

EGLN1: A Biomarker of Poor Prognosis of Cervical Cancer and a Target of Treatment.

Objective: To conduct bioinformatics analysis on the prognostic effect, mechanism of action, and drug sensitivity of Egl-9 family hypoxia-inducible factor 1 (EGLN1) expression on cervical cancer. Methods: Bioinformatics were obtained from Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), and the human cancer metastasis database (HCMDB), and the effect of EGLN1 expression level on the prognosis of cervical cancer was comprehensively analyzed. The protein-protein interaction network was constructed by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and the possible mechanism of EGLN1 affecting the prognosis of cervical cancer was discussed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. In addition, Gene Set Cancer Analysis (GSCALite) was used to predict sensitive drugs online. Results: The higher the expression level of EGLN1, the shorter the tumor-free survival time and overall survival time of cervical cancer. The higher the stage of cervical cancer, the higher the expression level of EGLN1. The expression of EGLN1 affects the degree of immune infiltration, the variation of somatic copy number, and the level of N6-methyladenosine (m6A) modification in cervical cancer. COX regression model suggested that EGLN1 was an independent prognostic factor of cervical cancer. Conclusions: The high expression of EGLN1 in cervical cancer is an independent risk factor for the prognosis of cervical cancer, which affects the prognosis of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) through different signal pathways. It is expected to be used to predict the sensitive anticancer drugs for the treatment of cervical cancer.

Circulating long non-coding RNA EWSAT1 acts as a liquid biopsy marker for esophageal squamous cell carcinoma: A pilot study

The widespread public health problem of esophageal squamous cell carcinoma (ESCC) is the cause of an increasing number of deaths each year due to delayed diagnosis. Therefore, we require specific and sensitive new biomarkers to manage ESCC better. The detection of diseases, such as cancer, can now be achieved through non-invasive circulating blood-based methods. Blood-based circulating non-coding RNAs, such as miRNA and lncRNA, have been extensively used as valuable markers for lung, esophageal, and breast cancer diagnostic purposes, as quoted in our previous research. Herein, we investigated the role of novel long non-coding RNA EWSAT1 as a blood-based liquid biopsy biomarker for the ESCC. Our findings indicate that EWSAT1 lncRNA has an increased tumor suppressive activity in ESCC, as it reduces by ∼2.59-fold relative to healthy controls. Moreover, we established that EWSAT1 expression can significantly distinguish between clinicopathological characteristics, including age, gender, and lifestyle choices such as smoking, alcohol consumption, and drinking hot beverages among patients with ESCC and healthy individuals. In addition, the expression levels of lncRNA EWSAT1 could distinguish between individuals with more advanced ESCC cancer and those without it, as illustrated by the ROC curve (AUC = 0.7174, 95 % confidence intervals = 0.5901 to 0.8448, p-value = 0.001). Our in-silico prediction methods demonstrated that miR-873-5p is the direct target of EWSAT1, which competes with the tumor suppressor candidate 3 (TUSC3) and EGL-9 family hypoxia-inducible factor 3 (EGLN3) mRNAs through a sponging mechanism, creating the EWSAT1/miR-873-5p/mRNA axis. We have analyzed the role of EWSAT1 in various cellular processes and signaling pathways, including mTOR, Wnt, and MAPK signaling pathways. Circulating EWSAT1 can be used as a liquid biopsy marker for diagnosis of ESCC and has the potential to serve as an effective therapeutic biomarker, according to this pilot study.

Hypoxia with or without Treadmill Exercises Affects Slow-Twitch Muscle Atrophy and Joint Destruction in a Rat Model of Rheumatoid Arthritis.

The effects of treadmill running under hypoxic conditions on joints and muscles of collagen-induced arthritis (CIA) rats were investigated. CIA rats were divided into normoxia no-exercise, hypoxia no-exercise (Hypo-no), and hypoxia exercise (Hypo-ex) groups. Changes were examined on days 2 and 44 of hypoxia with or without treadmill exercises. In the early stage of hypoxia, the expression of hypoxia-inducible factor (HIF)-1α increased in the Hypo-no and Hypo-ex groups. The expression of the egl-9 family hypoxia-inducible factor 1 (EGLN1) and vascular endothelial growth factor (VEGF) in the Hypo-ex group also increased. Under sustained hypoxia, the Hypo-no and Hypo-ex groups did not show increased expression of HIF-1α or VEGF, but p70S6K levels were elevated. Histologically, joint destruction was alleviated in the Hypo-no group, the loss of muscle weight in slow-twitch muscles was prevented, and muscle fibrosis was suppressed. In the Hypo-ex group, the preventive effect of a reduction in the slow-twitch muscle cross-sectional area was enhanced. Thus, chronic hypoxia in an animal model of rheumatoid arthritis controlled arthritis and joint destruction and prevented slow-twitch muscle atrophy and fibrosis. The combination of hypoxia with treadmill running further enhanced the preventive effects on slow-twitch muscle atrophy.

Modulation of miR-205/ EGLN2 by rosuvastatin mitigates colistin-induced nephrotoxicity in rats: Involvement of ATF4/ CHOP and Nrf2 pathways

Although the beneficial role of microRNA has been investigated thoroughly, the reno-protective role of microRNA-205 (miR-205) against colistin-induced nephrotoxicity has not yet been tackled. Hence, our study sought to study the possible modulatory effect of rosuvastatin on miR-205 and its downstream target, Egl-9 family hypoxia-inducible factor 2 (EGLN2) to combat oxidative and endoplasmic reticulum (ER) stresses as pivotal contributors to colistin-associated renal injury. Rats were randomly divided into four groups; normal, colistin (300 000 IU/Kg/day; i.p), colistin pretreated with rosuvastatin (10 mg/kg; p.o) and colistin pretreated with rosuvastatin (20 mg/kg; p.o) for 6 successive days. Pretreatment with rosuvastatin attenuated renal injury induced by colistin and enhanced kidney function with a marked reduction in renal injury markers, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Besides, rosuvastatin upregulated renal miR-205 expression and suppressed gene expression of EGLN2. In addition, it downregulated ER stress-related genes (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)) along with caspases 12 and 3. It also induced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) as detected by immunohistochemical examination besides increased renal antioxidants, reduced glutathione, and superoxide dismutase. In conclusion, rosuvastatin triggered a series of protective mechanisms against colistin-induced nephrotoxicity through modulating miR-205 and EGLN2 expression. Rosuvastatin suppressed ATF4/ CHOP trajectory and activated the Nrf2 pathway to substantiate its antioxidant and anti-apoptotic capacities.

Effects of idiopathic erythrocytosis on the left ventricular diastolic functions and the spectrum of genetic mutations: A case control study.

Background:We have aimed at exposing left ventricular diastolic functions and the presence of known genetic mutations for familial erythrocytosis, in patients who exhibit idiopathic erythrocytosis.Methods:Sixty-four patients with idiopathic erythrocytosis (mean age, 46.4 ± 2.7 years) and 30 age-matched healthy subjects were prospectively evaluated. The regions of interest of the erythropoietin receptor, hemoglobin beta-globin, von Hippel-Lindau, hypoxia-inducible factor 2 alpha, and Egl-9 family hypoxia-inducible factor genes were amplified by PCR. Left ventricular (LV) mass was measured by M-mode and 2-dimensional echocardiography. LV diastolic functions were assessed by conventional echocardiography and tissue Doppler imaging.Results:As a result of genetic analyses, genetic mutations for familial erythrocytosis were detected in 5 patients. It has been observed in our study that the risk of cardiovascular disorders is higher in patients. Interventricular septum thickness, left atrial diameter, and some diastolic function parameters such as deceleration time and isovolumetric relaxation time have been found to be significantly higher in idiopathic erythrocytosis group than in the controls.Conclusion:This study has shown that LV diastolic functions were impaired in patients with idiopathic erythrocytosis. In this patient group with increased risk of cardiovascular disorders, the frequent genetic mutations have been detected in 5 patients only. Therefore, further clinical investigations are needed as novel genetic mutations may be discovered in patients with idiopathic erythrocytosis because of cardiovascular risk.

A novel hypoxia-driven gene signature that can predict the prognosis of hepatocellular carcinoma

ABSTRACT Hypoxia environment exists in already started hepatocellular carcinoma (HCC) and promotes its progression by driving changes in the gene expression profiles of cells. However, the status of hypoxia-driven genes in HCC is largely unknown. In the present study, 368 HCC tissues from The Cancer Genome Atlas were divided into high and low hypoxia groups according to their hypoxia signatures. A total of 1,142 differentially expressed genes (DEGs) were identified between the two groups, and 34 of these DEGs were highly expressed in HCC tissues compared with adjacent tissues, especially in HCC tissues from patients with stage III–IV HCC. After constructing a protein–protein interaction network and applying the least absolute shrinkage and selection operator Cox regression method for 34 DEGs, a three-gene signature (complement factor H related 3 [CFHR3], egl-9 family hypoxia inducible factor 3 [EGLN3], and chromogranin A [CHGA]) was constructed and had prognostic value to predicted outcome of patients with HCC. This three-gene signature was suitable for classifying patients with HCC in the International Cancer Genome Consortium. CFHR3 shows remarkable diagnostic value in HCC. Hypoxia decreased CFHR3 expression, but increased HCC cell proliferation and motility. Overexpression of CFHR3 in HCC cells under hypoxia reversed the stimulatory effects of hypoxia and suppressed cell proliferation and metastasis in vivo. In conclusion, we identified a novel hypoxia-driven gene signature (CFHR3, EGLN3, and CHGA) for reliable prognostic prediction of HCC, and demonstrated that overexpression of CFHR3 may be a potential strategy to overcome hypoxia and treat HCC.

Genome-Wide Knockout Screen Identifies EGLN3 Involving in Ammonia Neurotoxicity.

Hepatic encephalopathy (HE) is a brain dysfunction associated with poor quality of life, increased morbidity and mortality. The pathogenesis of HE is still not fully clarified and effective therapeutic strategies are imperative. Among multiple factors that contribute to the pathophysiological process of HE, ammonia neurotoxicity is thought to be central in the pathogenesis of HE. Therefore, in this study, we subjected SH-SY5Y cells to ammonia insult and performed a pooled genome-wide CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) knockout screen to unveil the underlying molecular mechanisms of ammonia neurotoxicity and discover new potential therapeutic targets for HE. We found that EGLN3 (egl-9 family hypoxia-inducible factor 3) UCP3,GTPBP5, OR4D11 and SDR9C7 with 6 unique sgRNAs may contribute to protection against ammonia injury, while EGLN3 may be most related to ammonia resistance. We knocked down EGLN3 by transfecting neurons with specific shRNA lentivirus and confirmed that EGLN3 knockdown decreased ammonia-induced caspase-3 activation and apoptosis. We also demonstrated that EGLN3 knockdown ameliorated ammonia induced decreased expression of Bcl-2, increased expression of Bax and inhibited release of cytochrome c into the cytosol in neurons, suggesting that EGLN3 inhibition protected against ammonia induced apoptosis through mitochondrial dependent apoptosis pathway. Future therapeutic strategies regulating EGLN3 may be applied to the management of HE.

Evolution, characterization, and expression profile of Egl-9 family hypoxia-inducible factor (egln) in rainbow trout (Oncorhynchus mykiss) under hypoxia stress

Egl-9 family hypoxia-inducible factor (egln), an oxygen-sensing enzyme family, has been thoroughly characterized in mammals and certain fishes, but there is few research on its involvement in reproductive development and hypoxic stress in rainbow trout. In this study, we investigated the gene structure, physicochemical properties, and evolutionary connection of the egln gene family. The expression profile of egln gene family and their regulatory mechanism were explored using bioinformatics analysis and hypoxia treatment experiments. Five egln genes were discovered in the rainbow trout genome in this investigation (egln1, egln2a, egln2b, egln3a, and egln3b). Domain prediction revealed that all egln proteins have p4hc conserved domains, and phylogenetic analysis revealed that rainbow trout egln2 and egln3 were closely related to Atlantic salmon. The results of real-time quantitative PCR (RT-qPCR) showed that egln genes were generally expressed in all detected tissues, and higher in the ovary, testis, and brain in normoxia. Under hypoxia, the expression level of eglns was significantly down-regulated in most tissues except the liver. Our research contributes to future research on the functional properties of egln genes, as well as the evolution of teleosts and the impact of hypoxia on biological immunity.

EGLN1 induces tumorigenesis and radioresistance in nasopharyngeal carcinoma by promoting ubiquitination of p53 in a hydroxylase-dependent manner.

Egl-9 Family Hypoxia Inducible Factor 1 (EGLN1) is a proline hydroxylase mediating degradation of hypoxia-inducible factor α (HIFα) through the ubiquitination system. Studies have indicated an essential role for EGLN1 in angiogenesis and tumorigenesis. However, there is no consensus on the regulation of EGLN1 and its mechanism of action on nasopharyngeal carcinoma (NPC). This study explored the association of the expression of EGLN1 with characteristics of NPC tumors and its underlying mechanism. We found that the expression of EGLN1 showed a positive correlation with tumor T classification and clinical staging of patients with NPC. EGLN1 could promote cell proliferation, invasion and migration, and even enhance the cancer stem cells (CSCs) prosperity and radioresistance of NPC cells. Mechanistically, EGLN1 facilitated degradation of tumor protein p53 through the ubiquitination system. This effect could be weakened in the presence of dimethyloxalylglycine (DMOG), suggesting that EGLN1 down-regulated p53 based on its hydroxylase activity. In conclusion, overexpression of EGLN1 promoted oncogenesis and induced a CSC-like phenotype in NPC cells, then enhancing the ability for radioresistance by interacting with p53 in a hydroxylase-dependent manner. Thus, EGLN1 might serve as a potential therapeutic target for NPC.

Tumor innervation is triggered by endoplasmic reticulum stress.

Nerve infiltration in the tumor microenvironment is emerging as a promoter of cancer progression that could be targeted in therapies, but the mechanisms initiating tumor innervation remain to be elucidated. Here we report that endoplasmic reticulum (ER) stress in cancer cells is transmitted to neuronal cells, resulting in neurite outgrowth and tumor innervation. In vitro, the induction of ER stress in various human cancer cells resulted in the synthesis and release of the precursor for brain-derived neurotrophic factor (proBDNF) through a mechanism dependent on the transcription factor X-box binding protein 1 (XBP1). Cancer cell-released proBDNF was found to mediate the transmission of ER stress to neurons, resulting in the stimulation of neurite outgrowth. Next-generation sequencing indicated the increased expression of the Egl-9 family hypoxia inducible factor 3 (EGLN3) that was mediated by c-MYC and necessary to neurite outgrowth induced by proBDNF. In orthotopic tumor xenograft, ER stress stimulated XBP1 and proBDNF expression as well as tumor innervation. Anti-proBDNF antibody inhibited both tumor innervation and cancer progression induced by ER stress. Interestingly, the chemotherapeutic drug 5-Fluorouracil (5-FU) was found to induce ER stress and tumor innervation, and this effect was inhibited by anti-proBDNF antibody. Finally, in human tumors, cancer tissues with nerve infiltration expressed high XBP1 and proBDNF while EGLN3 was upregulated in infiltrated nerves. This study reveals that ER stress participates in tumor innervation through the release of proBDNF and that targeting this pathway could be used in future therapies.

Discovery and construction of prognostic model for clear cell renal cell carcinoma based on single-cell and bulk transcriptome analysis.

BackgroundClear cell renal cell carcinoma (ccRCC) is the most common malignant kidney tumor in adults. Single-cell transcriptome sequencing can provide accurate gene expression data of individual cells. Integrated single-cell and bulk transcriptome data from ccRCC samples provide comprehensive information, which allows the discovery of new understandings of ccRCC and the construction of a novel prognostic model for ccRCC patients.MethodsSingle-cell transcriptome sequencing data was preprocessed by using the Seurat package in R software. Principal component analysis (PCA) and the t-distributed stochastic neighbor embedding (t-SNE) algorithm were used to perform cluster classification. Two subtypes of cancer cells were identified, pseudotime trajectory analysis and gene ontology (GO) analysis were conducted with the monocle and clusterProfiler packages. Two novel cancer cell biomarkers were identified according to the single-cell sequencing and were confirmed by The Cancer Genome Atlas (TCGA) data. T cell-related marker genes according to single-cell sequencing were screened by a combination of Kaplan-Meier (KM) analysis, univariate Cox analysis, least absolute shrinkage and selection operator (Lasso) regression and multivariate Cox analysis of TCGA data. Four survival predicting genes were screened out to develop a risk score model. A nomogram consisting of the risk score and clinical information was constructed to predict the prognosis for ccRCC patients.ResultsA total of 5,933 cells were included in the study after quality control. Fifteen cell clusters were classified by PCA and t-SNE algorithm. Two clusters of cancer cells with distinct differentiation status were identified. Besides, GO analysis revealed that biological processes were different between the two subgroups. Egl-9 family hypoxia-inducible factor 3 (EGLN3) and nucleolar protein 3 (NOL3) were specifically expressed in cancer cell clusters, bulk RNA sequencing data from TCGA confirmed their high expression in ccRCC tissues. GTSE1, CENPF, SMC2 and H2AFV were screened out and applied to the construction of risk score model. A nomogram was generated to predict prognosis of ccRCC by combing the risk score and clinical parameters.ConclusionsWe integrated single-cell and bulk transcriptome data from ccRCC in this study. Two subtypes of ccRCC cells with different biological characteristics and two potential biomarkers of ccRCC were discovered. A novel prognostic model was constructed for clinical application.

Myoblast differentiation of C2C12 cell may related with oxidative stress.

Muscle is a contractile tissue responsible for maintaining posture and the movement of all parts of the body. Prolonged oxidizative stress can lead to the damage of cells, tissues, and organs. In this study, we investigated the possibility of oxidative stress in the process of myoblast differentiation of C2C12 cells. First, the myoblast differentiation model of C2C12 cells was constructed and verified by Giemsa staining. The expression of hypoxia inducible factor1-alpha (HIF1-α), hypoxia inducible factor1-beta (HIF1-β), Von Hippel-Lindau (VHL), lysyl oxidase (Lox), EGL-9 family hypoxia-inducible factor 1 (EGLN1), proline 4-hydroxylase alpha 1 (P4HA1) and heme oxygenase-1 (HOMX1) in the process of myoblast differentiation was verified by in vitro experiments and Gene Expression Omnibus (GEO) bioinformatic analysis. We found that with the increased expression of myogenic factor 5 (MYF5), myogenic differentiation 1 (MYOD1), and Desmin, myotube fusion became more obvious during the process of C2C12 cell differentiation. Both experimental and GEO analysis indicated that the expression of HIF1-α, HIF1-β, VHL, LOX, EGLN1 and P4HA1 increased, and the expression of HOMX1 decreased during myogenic differentiation. Therefore, we suggest that the myoblast differentiation of C2C12 cells may be related to oxidative stress. Their possible relationship was proposed, though further studies are needed.

Genome-wide diversity analysis for signatures of selection of Bos indicus adaptability under extreme agro-climatic conditions of temperate and tropical ecosystems

Indigenous cattle breeds (Bos indicus) inhabited under diverse agroclimatic conditions may serve as a broad reservoir of genetic pool for identifying genes selected for local adaptation. The present study aimed at deciphering genomic diversity and identifying adaptation signatures of cattle breeds belonging to contrasting agro-climatic conditions: Siri and Ladakhi from cold hilly region; and Kankrej and Hallikar from hot arid and semi-arid regions, respectively. A total of 46 samples were genotyped using 777 K Illumina BovineHD BeadChip. The Principal Component Analysis brought together Hallikar and Kankrej, while Siri and Ladakhi formed a separate cluster. In contrast to the tropical cattle breeds, genetic variation was higher for temperate type. Linkage disequilibrium decay (r2 < 0.2) in hot semi-arid/arid adapted (71–103 kb) and temperate-adapted (218–222 kb) breeds revealed that BovineHD BeadChip can be used in predicting their genomic breeding values. Runs of homozygosity and FST based selection signatures were also identified in these cattle breeds. Novel hypoxia-related genes viz. egl-9 family hypoxia inducible factor, hypoxia inducible factor 1 subunit alpha inhibitor and heme oxygenase 1 were detected in temperate adapted breeds, while heat stress (heat shock protein family H (Hsp110) member 1 and BAG cochaperone 2 and immunity (TANK binding kinase 1) related genes were identified in selection sweeps of tropical breeds. Gene ontology analysis identified several enriched terms for the genes in both hot semi-arid/arid and temperate adapted cattle breeds in ROH islands. The relevant adaptation signals found in the present study will help to establish new breeding opportunities with recognition of core genes.

Effect of EGLN1 Genetic Polymorphisms on Hemoglobin Concentration in Andean Highlanders

The physiological characteristics of Andean natives living at high altitudes have been investigated extensively, with many studies reporting that Andean highlanders have a higher hemoglobin (Hb) concentration than other highlander populations. It has previously been reported that positive natural selection has acted independently on the egl-9 family hypoxia inducible factor 1 (EGLN1) gene in Tibetan and Andean highlanders and is related to Hb concentration in Tibetans. However, no study has yet revealed the genetic determinants of Hb concentration in Andeans even though several single-nucleotide polymorphisms (SNPs) in EGLN1 have previously been examined. Therefore, we explored the relationship between hematological measurements and tag SNPs designed to cover the whole EGLN1 genomic region in Andean highlanders living in Bolivia. Our findings indicated that haplotype frequencies estimated from the EGLN1 SNPs were significantly correlated with Hb concentration in the Bolivian highlanders. Moreover, we found that an Andean-dominant haplotype related to high Hb level may have expanded rapidly in ancestral Andean highlander populations. Analysis of genotype data in an ~436.3 kb genomic region containing EGLN1 using public databases indicated that the population structure based on EGLN1 genetic markers in Andean highlanders was largely different from that in other human populations. This finding may be related to an intrinsic or adaptive physiological characteristic of Andean highlanders. In conclusion, the high Hb concentrations in Andean highlanders can be partly characterized by EGLN1 genetic variants.

Genome-Wide Gene-by-Smoking Interaction Study of Chronic Obstructive Pulmonary Disease.

Risk of chronic obstructive pulmonary disease (COPD) is determined by both cigarette smoking and genetic susceptibility, but little is known about gene-by-smoking interactions. We performed a genome-wide association analysis of 179,689 controls and 21,077 COPD cases from UK Biobank subjects of European ancestry recruited from 2006 to 2010, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degrees-of-freedom (df) test) as well as interaction effects alone (1-df interaction test). We sought to replicate significant results in COPDGene (United States, 2008-2010) and SpiroMeta Consortium (multiple countries, 1947-2015) data. We considered 2 smoking variables: 1) ever/never and 2) current/noncurrent. In the 1-df test, we identified 1 genome-wide significant locus on 15q25.1 (cholinergic receptor nicotinic β4 subunit, or CHRNB4) for ever- and current smoking and identified PI*Z allele (rs28929474) of serpin family A member 1 (SERPINA1) for ever-smoking and 3q26.2 (MDS1 and EVI1 complex locus, or MECOM) for current smoking in an analysis of previously reported COPD loci. In the 2-df test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (sphingomyelin phosphodiesterase 3, or SMPD3) and 19q13.2 (Egl-9 family hypoxia inducible factor 2, or EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, were replicated in COPDGene and SpiroMeta. We identified interaction effects at previously reported COPD loci; however, we failed to identify novel susceptibility loci.

ESC-sEVs Rejuvenate Aging Hippocampal NSCs by Transferring SMADs to Regulate the MYT1-Egln3-Sirt1 Axis

Tissue stem cell senescence leads to stem cell exhaustion, which results in tissue homeostasis imbalance and a decline in regeneration capacity. However, whether neural stem cell (NSC) senescence occurs and causes neurogenesis reduction during aging is unknown. In this study, mice at different ages were used to detect age-related hippocampal NSC (H-NSC) senescence, as well as the function and mechanism of embryonic stem cell-derived small extracellular vesicles (ESC-sEVs) in rejuvenating H-NSC senescence. We found a progressive cognitive impairment, as well as age-related H-NSC senescence, in mice. ESC-sEV treatment significantly alleviated H-NSC senescence, recovered compromised self-renewal and neurogenesis capacities, and reversed cognitive impairment. Transcriptome analysis revealed that myelin transcription factor 1 (MYT1) is downregulated in senescent H-NSCs but upregulated by ESC-sEV treatment. In addition, knockdown of MYT1 in young H-NSCs accelerated age-related phenotypes and impaired proliferation and differentiation capacities. Mechanistically, ESC-sEVs rejuvenated senescent H-NSCs partly by transferring SMAD family members 4 (SMAD4) and 5 (SMAD5) to activate MYT1, which downregulated egl-9 family hypoxia inducible factor 3 (Egln3), followed by activation of hypoxia inducible factor 2 subunit α (HIF-2α), nicotinamide phosphoribosyl transferase (NAMPT), and sirtuin 1 (Sirt1) successively. Taken together, our results indicated that H-NSC senescence caused cellular exhaustion, neurogenesis reduction, and cognitive impairment during aging, which can be reversed by ESC-sEVs. Thus, ESC-sEVs may be promising therapeutic candidates for age-related diseases.