scholarly journals Exposure to hypoxia causes stress erythropoiesis and downregulates immune response genes in spleen of mice

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Haijing Wang ◽  
Daoxin Liu ◽  
Pengfei Song ◽  
Feng Jiang ◽  
Xiangwen Chi ◽  
...  

Abstract Background The spleen is the largest secondary lymphoid organ and the main site where stress erythropoiesis occurs. It is known that hypoxia triggers the expansion of erythroid progenitors; however, its effects on splenic gene expression are still unclear. Here, we examined splenic global gene expression patterns by time-series RNA-seq after exposing mice to hypoxia for 0, 1, 3, 5, 7 and 13 days. Results Morphological analysis showed that on the 3rd day there was a significant increase in the spleen index and in the proliferation of erythroid progenitors. RNA-sequencing analysis revealed that the overall expression of genes decreased with increased hypoxic exposure. Compared with the control group, 1380, 3430, 4396, 3026, and 1636 genes were differentially expressed on days 1, 3, 5, 7 and 13, respectively. Clustering analysis of the intersection of differentially expressed genes pointed to 739 genes, 628 of which were upregulated, and GO analysis revealed a significant enrichment for cell proliferation. Enriched GO terms of downregulated genes were associated with immune cell activation. Expression of Gata1, Tal1 and Klf1 was significantly altered during stress erythropoiesis. Furthermore, expression of genes involved in the immune response was inhibited, and NK cells decreased. Conclusions The spleen of mice conquer hypoxia exposure in two ways. Stress erythropoiesis regulated by three transcription factors and genes in immune response were downregulated. These findings expand our knowledge of splenic transcriptional changes during hypoxia.

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 950-950
Author(s):  
Xu Zhang ◽  
Jihyun Song ◽  
Binal N. Shah ◽  
Jin Han ◽  
Taif Hassan ◽  
...  

Abstract Reticulocytosis in sickle cell disease (SCD) is driven by tissue hypoxia from hemolytic anemia and vascular occlusion. Gene expression changes caused by hypoxia and other factors during reticulocytosis may impact SCD outcomes. We detected 1226 differentially expressed genes in SCD reticulocyte transcriptome compared to normal Black controls. To assess the role of hypoxia-mediating HIFs from other regulation of changes of the SCD reticulocyte transcriptome, we compared differential expression in SCD to that in Chuvash erythrocytosis (CE), a disorder characterized by constitutive upregulation of HIFs in normoxia. Of the SCD differentially expressed genes, 28% were shared between CE and SCD and thus classified as HIF-mediated. The HIF-mediated changes were generally in genes promoting erythroid maturation. We found that genes encoding the response to endoplasmic reticulum stress generally lacked HIF mediation. We then investigated the clinical correlation of erythroid gene expression for the 1226 differentially expressed genes detected in SCD reticulocytes, using clinical measures and gene expression data previously profiled in peripheral blood mononuclear cells (PBMCs) of 157 SCD patients at the University of Illinois at Chicago (UIC). Normal PBMCs contain only a small number of erythroid progenitors, but in SCD or CE PBMCs the erythroid transcriptome is enriched due to elevated circulating erythroid progenitors from heightened erythropoiesis (PMID: 32399971). We applied deconvolution analysis to assess the clinical correlation of erythroid gene expression, using a 16-gene expression signature of erythroid progenitors previously identified in SCD PBMCs. Deconvolution analysis uses the proportion of cell/tissue or specific marker genes (here the erythroid specific 16-gene signature) to dissect gene expression variation in biological samples with cell/tissue type heterogeneity. We correlated, in the 157 UIC patients, erythroid gene expression with i) degree of anemia as indicated by hemoglobin concentration, ii) vaso-occlusive severe pain episodes per year, and iii) degree of hemolysis measured by a hemolysis index. The analysis identified 231 genes associated with at least one of the complications. Increased expression of 40 erythroid specific genes, including 15 HIF-mediated genes, was associated with all three complications. These 40 genes are all upregulated in SCD reticulocytes and correlated with low hemoglobin concentration, frequent severe pain episodes, and high hemolysis index, suggesting that these manifestations may share a relationship to stress erythropoiesis-driven transcriptional activity. Expression quantitative trait loci (eQTL) contain genetic polymorphisms that associate with gene expression level, which can be viewed as a natural experiment to investigate the causal relations between gene expression change and phenotypic outcomes. To assess the causal effect of erythroid gene expression, we tested association between erythroid eQTL and the clinical manifestations in 906 SCD patients from the Walk-PHaSST and PUSH cohorts. We first mapped erythroid eQTL in the 157 UIC patients, who were previously genotyped by array, applying deconvolution algorithm on the same PBMC data for the 1226 differential genes in SCD reticulocytes, and detected 54 distinct eQTL for 30 genes at 5% false discovery rate. After adjusting for multiple comparisons, we found that the C allele of rs16911905, located in the β-globin cluster and associated with increased erythroid expression of HBD (encodes δ-globin of hemoglobin A 2), significantly correlated with lower hemoglobin concentration (β=-0.064, 95% CI -0.092 - -0.036, P=6.7×10 -6). The C allele was also associated with higher hemolytic rate (P=0.031), less frequent pain episodes (P=0.045), and increased erythroid expression of HBB here encoding sickle β-globin (P=5.1x10 -5). The association of the C allele with lower hemoglobin concentration was then validated in 242 patients from the UIC cohort (β=-0.071, 95% CI -0.13 - -0.011, P=0.023), as was the trend of association with higher hemolytic rate (P=0.0031) and less pain episodes (P=0.034). Our findings reveal HIF- and non-HIF-mediated genes in SCD stress erythropoiesis, and identify novel clinical associations for a HBD eQTL. Our study highlights the correlation of altered erythroid gene expression with SCD hemolytic and vaso-occlusive manifestations. Disclosures Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy.


2019 ◽  
Vol 53 (2) ◽  
pp. 71-82 ◽  
Author(s):  
Dmytro O. Minchenko

AbstractObjective. The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes through changes in the expression of numerous regulatory genes.Methods. The expression level of HLA-DRA, HLA-DRB1, HLA-G, HLA-F, and NFX1 genes as well as miR-190b was measured in the blood of obese adolescents without signs of resistance to insulin and with insulin resistance in comparison with the group of relative healthy control individuals without signs of obesity.Results. It was shown that obesity without signs of insulin resistance is associated with upregulation of the expression level of HLA-DRA and HLA-DRB1 genes, but with down-regulation of HLA-G gene expression in the blood as compared to control group of relative healthy adolescents. At the same time, no significant changes were observed in the expression level of HLA-F and NFX1 genes in the blood of this group of obese adolescents. Development of insulin resistance in obese individuals leads to significant down-regulation of HLA-DRA, HLA-DRB1, HLA-G, and HLA-F gene expressions as well as to up-regulation of NFX1 gene as well as microRNA miR-190b in the blood as compared to obese patients without signs of insulin resistance.Conclusions. Results of this study provide evidence that obesity affects the expression of the subset of genes related to immune response in the blood and that development of insulin resistance in obese adolescents is associated with strong down-regulation of the expressions of HLA-DRA, HLA-DRB1, HLA-F, and HLA-G genes, which may be contribute to the development of obesity complications. It is possible that transcription factor NFX1 and miR-190b participate in downregulation of HLA-DRA gene expression in the blood of obese adolescents with insulin resistance.


2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Xiaoming Gong ◽  
Lewis Rubin

Abstract Objectives Carotenoid/retinoids status and metabolism are essential for normal placental and fetal development. Both deficiencies and excess of retinoids and some carotenoids are associated with adverse pregnancy outcomes, such as preeclampsia and preterm birth. A group of important genes involved in regulating carotenoid/retinoid metabolism and maternal to fetal transfer in human placenta. The objective of this study is to analyze (a) the expression of genes critical for regulating carotenoid/retinoid metabolism and maternal-fetal transport in human trophoblasts and (b) placental transcriptional profiles of these pathways in response to carotenoid exposure. Methods Human cytotrophoblasts (CTBs) were isolated from term placentas. CTB RNA was used to analyze the expression of genes involved in carotenoid/retinoid metabolism and pathways by qRT-PCT. First trimester-like trophoblasts (HTR-8/SVneo) were treated with either β-carotene or lycopene. RNAs were isolated and gene expression were analyzed by DNA microarrays. Results Human CTBs express retinoid metabolism and pathways-related genes, including Stra6, Lrat, Rdh5, Rdh10, Aldh1a1, Aldh1a2, Aldh1a3, Aldh8a1, Cyp26a1, and Cyp26b1, but not carotenoid metabolism genes, BCO1 and BCO2. Microarray analysis of placental gene expression profile revealed a total of 872 and 756 differentially expressed genes, respectively, compared to the control. Gene set enrichment analysis and functional annotation clustering was performed to characterize the genes differentially expressed in either β-carotene or lycopene-treated HTR-8/SVneo cells. Many known retinoid metabolism related genes and genes involved in regulation of retinoid signaling were found, and the expression profiles of these genes were markedly different in response to β-carotene treatments. Finally, the qRT-PCR and microarray analysis results showed similar gene expression patterns of carotenoid/retinoid metabolism and pathways. Conclusions These findings suggest that placental expression of genes involved in retinoid metabolism and transport in trophoblasts is critical for regulating retinoid homeostasis during placental and fetal development. Carotenoid exposure in early placental development, significantly modify the placenta gene expression related to retinoid pathways and maternal to fetal transfer. Funding Sources NIH HD421174.


2020 ◽  
Vol 32 (12) ◽  
pp. 1067
Author(s):  
Wangsheng Zhao ◽  
Eugene Quansah ◽  
Meng Yuan ◽  
Pengcheng Li ◽  
Chuanping Yi ◽  
...  

MicroRNAs (miRNAs) have emerged as potent regulators of gene expression and are widely expressed in biological systems. In reproduction, they have been shown to have a significant role in the acquisition and maintenance of male fertility, whereby deletion of Dicer in mouse germ cells leads to infertility. Evidence indicates that this role of miRNAs extends from the testis into the epididymis, controlling gene expression and contributing to regional variations in gene expression. In this study, RNA sequencing technology was used to investigate miRNA expression patterns in the yak epididymis. Region-specific miRNA expression was found in the yak epididymis. In all, 683 differentially expressed known miRNAs were obtained; 190, 186 and 307 differentially expressed miRNAs were identified for caput versus corpus, corpus versus cauda and caput versus cauda region pairs respectively. Kyoto Encyclopedia of Genes and Genomes results showed endocytosis as the most enriched pathway across region pairs, followed by protein processing in the endoplasmic reticulum, phagosome, spliceosome and biosynthesis of amino acids in region pair-specific hierarchical order. Gene ontology results showed varied enrichment in terms including cell, biogenesis, localisation, binding and locomotion across region pairs. In addition, significantly higher miR-34c expression was seen in the yak caput epididymidis relative to the corpus and cauda epididymidis.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5204-5204
Author(s):  
Hong Jiang ◽  
Cheryl Wade-Harris ◽  
Megan Lim ◽  
Laxmi Baxi ◽  
Mitchell S. Cairo

Abstract It has been recognized that dysfunction of CB immune system is in part due to the immaturity of CB cellular immunity (Cairo, Blood,1997). The molecular mechanisms associated with the immaturity of CB cellular immunity including DC subset remain to be defined. The maturation status of DC greatly influences its antigen presentation capacity. Recently, we have utilized oligonucleotide microarray to demonstrate differential gene expression profiles of CB vs APB Mo (Jiang/Cairo, JI, 2004). In the current study, differential expressed genes and proteins were examined in Mo-derived CB vs. APB DC during DC developmental stages: Mo, immature DC (iDC) and mDC, by utilizing oligonucleotide microarray and proteomics. Briefly, Mo isolated from CB or APB and cultured for 8 days with GM-CSF/IL-4 (iDC) and further stimulated with LPS (mDC). Oligonucleotide microarray was carried out using U133A gene chip (Affymetrix). The representative differentially expressed genes resulted from microarray analysis were selected and analyzed by quantitative RT-PCR (Roche). The proteomic technique was conducted by liquid chromatography (LC) and mass spectrometry (MS) (Lim, Mol Cell Proteomics, 2006). The differentially expressed proteins were compared in CB vs. APB for iDC and mDC. We identified different gene expression patterns that were significantly lower in CB vs. APB in different stages during DC differentiation: Mo, iDC and mDC. These differentially expressed genes included RELA (5F), JUNB (6F), IRF-1 (3F) in Mo; CREB5 (3F), MAP7 (5F), IL1R2 (6F) in iDC; and HLA-DQA1 (4F), CD80 (3F), IRF-5 (3F) in mDC. The proteomic studies demonstrated Tyrosine Kinase Fer (12.5F), Actin regulator 3 (2.5F), Rap guanine nucleotide exchange factor 1 (2.4F) and Myeloid cell nuclear differentiation antigen (1.5F) were expressed higher in APB vs.CB iDC, while MAX binding protein MNT (5.5F), IRS2 (2.2F) and Zinc-Finger Proteins (514, 212, 462) (3–14F) were expressed higher in CB vs. APB iDC. Further, the proteomic results also indicated other Zinc-Finger Proteins (292, 221, 474) (2–5F), Fibrillin 1 precursor (2.5F) and interleukin-4 (7.7F) were expressed higher in APB vs. CB mDC. In contrast, cyclin I (3F), Rb-like protein 2 (4.35 F) and PKC theta (2F) were significantly lower in APB vs. CB DC. Moreover, the comparison of CB vs. APB DC antigen presenting activity by ELISPOT was performed and the influenza-peptide loaded CB-mDC demonstrated weaker ability to induce T cells to produce IFNg compared with APB-mDC. In summary, these differentially expressed genes in Mo (RELA, JUN) may play key roles in initiating Mo differentiation toward DC. The increased expression of genes in APB vs. CB iDC, like CREB5, IL1R2, may be involved in mediating maturation process of iDC to mDC. Lastly, the elevated expression of genes in APB vs. CB mDC, such as HLA-DQA1, CD80, IRF5 among others, may be likely to control mDC functionality as demonstrated by weaker antigen presenting activity of CB vs. APB mDC. We postulate that decreased expression of specific genes in CB vs. APB DC during DC developmental stages may in part be responsible for the lack of maturity of CB, and ultimately may partially be responsible for differential CB vs. APB innate and adaptive immunity.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5078-5078
Author(s):  
Monika Belickova ◽  
Alzbeta Vasikova ◽  
Eva Budinska ◽  
Jaroslav Cermak

Abstract Myelodysplatic syndrome (MDS) represents a heterogeneous group of clonal disorders with ineffective hematopoiesis that is characterized by dysplasia and peripheral cytopenia of one or more cell lineages. We studied gene expression profiles in CD34+ cells of 42 MDS patients and 6 healthy controls using Illumina cDNA microarray technology. Nine patients had RA, 7 patients had RCMD, 17 patients had RAEB and 9 had RAEB-T. CD34+ cells were isolated from bone marrow samples using MACS magnetic columns. The quality of total extracted RNA was confirmed with the Agilent Bioanalyzer 2100. 200ng of total RNA was amplified using Illumina RNA amplification kit. cRNA targets were hybridized on the Sentrix HumanRef-8 BeadChips (> 24 000 probes), which were scanned on the Illumina BeadStation 500. The data were pre-processed and normalized by lumi R package designed to preprocess the Illumina microarray data. Normalized data were filtered by detection p-value <0.01, resulting in total number of 10 091 genes. This gene set was tested for differential expression between clinical groups and control group. For this purpose, statistical testing by ANOVA with correction for multiple testing problem by Bayesian thresholding was performed. Additionally, analysis by random-forests (RAFT) was performed. Significant genes from both analyses were merged resulting in 332 differentially expressed genes detected. Out of these, 79 genes showed ≥2.5 fold changes in gene expression between controls and all MDS groups (22 up-regulated and 57 down-regulated). Our findings were confirmed by real-time quantitative PCR for several genes (TaqMan Gene Expression Assays). We used DAVID database to annotate 79 selected genes: 8 of 22 up-regulated genes in MDS patients were recognized to play a role in regulation of transcription (LEO1, E2F6 and several zing finger proteins). A half of these over-expressed genes could not be annotated due to still unknown biological function. Within the set of the down-regulated genes in MDS patients those biological processes were predominantly detected: cell differentiation (KLF4, FOSL2, STK17B, BCL3, SNF1LK, ID2 etc.), response to stress (CXCL12, SMAD7, CYGB, etc.) and cell proliferation (MXD1, OSM, FTH1, KLF10 etc.). In the set of 31 genes with 5 fold decreased expression, we identified 8 genes involved in B-cell development. (VPREB1, VPREB3, CD79A, EBI2, LEF1, CXCL12, CTGF, GALNAC4S-6ST). RAFT analysis was performed also in the set of 332 statistically differentially expressed genes in order to evaluate accuracy of grouping the patients according their diagnosis. We detected strong heterogeneity in gene expression patterns within the MDS patients, especially in the RAEB group reflecting clinical diversity of MDS. Clustering analysis (Spearman correlation) showed that most of the RAEB-2 patients (7 out of 9) were clustered together with REAB-T whereas RAEB-1 clustered with RCMD or RA. These results underline the need of distinguishing RAEB-1 and RAEB-2 diagnosis according to WHO classification system, since their expression profiles are significantly different.


2020 ◽  
Vol 21 (21) ◽  
pp. 7838
Author(s):  
Grzegorz A. Czapski ◽  
Yuhai Zhao ◽  
Walter J. Lukiw ◽  
Joanna B. Strosznajder

Acute systemic inflammatory response (SIR) triggers an alteration in the transcription of brain genes related to neuroinflammation, oxidative stress and cells death. These changes are also characteristic for Alzheimer’s disease (AD) neuropathology. Our aim was to evaluate gene expression patterns in the mouse hippocampus (MH) by using microarray technology 12 and 96 h after SIR evoked by lipopolysaccharide (LPS). The results were compared with microarray analysis of human postmortem hippocampal AD tissues. It was found that 12 h after LPS administration the expression of 231 genes in MH was significantly altered (FC > 2.0); however, after 96 h only the S100a8 gene encoding calgranulin A was activated (FC = 2.9). Gene ontology enrichment analysis demonstrated the alteration of gene expression related mostly to the immune-response including the gene Lcn2 for Lipocalin 2 (FC = 237.8), involved in glia neurotoxicity. The expression of genes coding proteins involved in epigenetic regulation, histone deacetylases (Hdac4,5,8,9,11) and bromo- and extraterminal domain protein Brd3 were downregulated; however, Brd2 was found to be upregulated. Remarkably, the significant increase in expression of Lcn2, S100a8, S100a9 and also Saa3 and Ch25h, was found in AD brains suggesting that early changes of immune-response genes evoked by mild SIR could be crucial in AD pathogenesis.


2006 ◽  
Vol 74 (6) ◽  
pp. 3633-3642 ◽  
Author(s):  
Sinem Beyhan ◽  
Anna D. Tischler ◽  
Andrew Camilli ◽  
Fitnat H. Yildiz

ABSTRACT Differences in whole-genome expression patterns between the classical and El Tor biotypes of Vibrio cholerae O1 were determined under conditions that induce virulence gene expression in the classical biotype. A total of 524 genes (13.5% of the genome) were found to be differentially expressed in the two biotypes. The expression of genes encoding proteins required for biofilm formation, chemotaxis, and transport of amino acids, peptides, and iron was higher in the El Tor biotype. These gene expression differences may contribute to the enhanced survival capacity of the El Tor biotype in environmental reservoirs. The expression of genes encoding virulence factors was higher in the classical than in the El Tor biotype. In addition, the vieSAB genes, which were originally identified as regulators of ctxA transcription, were expressed at a fivefold higher level in the classical biotype. We determined the VieA regulon in both biotypes by transcriptome comparison of wild-type and vieA deletion mutant strains. VieA predominantly regulates gene expression in the classical biotype; 401 genes (10.3% of the genome), including those encoding proteins required for virulence, exopolysaccharide biosynthesis, and flagellum production as well as those regulated by σE, are differentially expressed in the classical vieA deletion mutant. In contrast, only five genes were regulated by VieA in the El Tor biotype. A large fraction (20.8%) of the genes that are differentially expressed in the classical versus the El Tor biotype are controlled by VieA in the classical biotype. Thus, VieA is a major regulator of genes in the classical biotype under virulence gene-inducing conditions.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
L. Criado-Mesas ◽  
N. Abdelli ◽  
A. Noce ◽  
M. Farré ◽  
J. F. Pérez ◽  
...  

AbstractThere is a high interest on gut health in poultry with special focus on consequences of the intestinal diseases, such as coccidiosis and C. perfringens-induced necrotic enteritis (NE). We developed a custom gene expression panel, which could provide a snapshot of gene expression variation under challenging conditions. Ileum gene expression studies were performed through high throughput reverse transcription quantitative real-time polymerase chain reaction. A deep review on the bibliography was done and genes related to intestinal health were selected for barrier function, immune response, oxidation, digestive hormones, nutrient transport, and metabolism. The panel was firstly tested by using a nutritional/Clostridium perfringens model of intestinal barrier failure (induced using commercial reused litter and wheat-based diets without exogenous supplementation of enzymes) and the consistency of results was evaluated by another experiment under a coccidiosis challenge (orally gavaged with a commercial coccidiosis vaccine, 90× vaccine dose). Growth traits and intestinal morphological analysis were performed to check the gut barrier failure occurrence. Results of ileum gene expression showed a higher expression in genes involved in barrier function and nutrient transport in chickens raised in healthy conditions, while genes involved in immune response presented higher expression in C.perfringens-challenged birds. On the other hand, the Eimeria challenge also altered the expression of genes related to barrier function and metabolism, and increased the expression of genes related to immune response and oxidative stress. The panel developed in the current study gives us an overview of genes and pathways involved in broiler response to pathogen challenge. It also allows us to deep into the study of differences in gene expression pattern and magnitude of responses under either a coccidial vaccine or a NE.


BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Aliki Xanthopoulou ◽  
Javier Montero-Pau ◽  
Belén Picó ◽  
Panagiotis Boumpas ◽  
Eleni Tsaliki ◽  
...  

Abstract Background Summer squash (Cucurbita pepo: Cucurbitaceae) are a popular horticultural crop for which there is insufficient genomic and transcriptomic information. Gene expression atlases are crucial for the identification of genes expressed in different tissues at various plant developmental stages. Here, we present the first comprehensive gene expression atlas for a summer squash cultivar, including transcripts obtained from seeds, shoots, leaf stem, young and developed leaves, male and female flowers, fruits of seven developmental stages, as well as primary and lateral roots. Results In total, 27,868 genes and 2352 novel transcripts were annotated from these 16 tissues, with over 18,000 genes common to all tissue groups. Of these, 3812 were identified as housekeeping genes, half of which assigned to known gene ontologies. Flowers, seeds, and young fruits had the largest number of specific genes, whilst intermediate-age fruits the fewest. There also were genes that were differentially expressed in the various tissues, the male flower being the tissue with the most differentially expressed genes in pair-wise comparisons with the remaining tissues, and the leaf stem the least. The largest expression change during fruit development was early on, from female flower to fruit two days after pollination. A weighted correlation network analysis performed on the global gene expression dataset assigned 25,413 genes to 24 coexpression groups, and some of these groups exhibited strong tissue specificity. Conclusions These findings enrich our understanding about the transcriptomic events associated with summer squash development and ripening. This comprehensive gene expression atlas is expected not only to provide a global view of gene expression patterns in all major tissues in C. pepo but to also serve as a valuable resource for functional genomics and gene discovery in Cucurbitaceae.


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