scholarly journals Premature Activation of Immune Transcription Programs in Autoimmune-Predisposed Mouse Embryonic Stem Cells and Blastocysts

2020 ◽  
Vol 21 (16) ◽  
pp. 5743
Author(s):  
Oktay Kirak ◽  
Eugene Ke ◽  
Kevin Y. Yang ◽  
Anna Schwarz ◽  
Lars Plate ◽  
...  
Keyword(s):  
Histone Modifications ◽  
Genetic Predisposition ◽  
Autoimmune Diabetes ◽  
Es Cells ◽  
Embryonic Stem ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Immune Functions ◽  
Active Expression

Autoimmune diabetes is a complex multifactorial disease with genetic and environmental factors playing pivotal roles. While many genes associated with the risk of diabetes have been identified to date, the mechanisms by which external triggers contribute to the genetic predisposition remain unclear. Here, we derived embryonic stem (ES) cell lines from diabetes-prone non-obese diabetic (NOD) and healthy C57BL/6 (B6) mice. While overall pluripotency markers were indistinguishable between newly derived NOD and B6 ES cells, we discovered several differentially expressed genes that normally are not expressed in ES cells. Several genes that reside in previously identified insulin-dependent diabetics (Idd) genomic regions were up-regulated in NOD ES cells. Gene set enrichment analysis showed that different groups of genes associated with immune functions are differentially expressed in NOD. Transcriptomic analysis of NOD blastocysts validated several differentially overexpressed Idd genes compared to B6. Genome-wide mapping of active histone modifications using ChIP-Seq supports active expression as the promoters and enhancers of activated genes are also marked by active histone modifications. We have also found that NOD ES cells secrete more inflammatory cytokines. Our data suggest that the known genetic predisposition of NOD to autoimmune diabetes leads to epigenetic instability of several Idd regions.

scholarly journals Bioinformatics-based Screening of Key Genes for Saponin Metabolism in Quinoa

2021 ◽  
Author(s):  
Chengang Guo ◽  
Zhimin wei ◽  
Wei Lyu ◽  
Yanlou Geng
Keyword(s):  
Differentially Expressed Genes ◽  
Principal Component ◽  
Enrichment Analysis ◽  
Hierarchical Cluster ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Differential Analysis ◽  
Rna Seq ◽  
Protein Coding ◽  
Key Genes

Abstract Quinoa saponins have complex, diverse and evident physiologic activities. However, the key regulatory genes for quinoa saponin metabolism are not yet well studied. The purpose of this study was to explore genes closely related to quinoa saponin metabolism. In this study, the significantly differentially expressed genes in yellow quinoa were firstly screened based on RNA-seq technology. Then, the key genes for saponin metabolism were selected by gene set enrichment analysis (GSEA) and principal component analysis (PCA) statistical methods. Finally, the specificity of the key genes was verified by hierarchical clustering. The results of differential analysis showed that 1654 differentially expressed genes were achieved after pseudogenes deletion. Therein, there were 142 long non-coding genes and 1512 protein-coding genes. Based on GSEA analysis, 116 key candidate genes were found to be significantly correlated with quinoa saponin metabolism. Through PCA dimension reduction analysis, 57 key genes were finally obtained. Hierarchical cluster analysis further demonstrated that these key genes can clearly separate the four groups of samples. The present results could provide references for the breeding of sweet quinoa and would be helpful for the rational utilization of quinoa saponins.

scholarly journals LINC01018 and SMIM25 sponged miR-182-5p in endometriosis revealed by the ceRNA network construction

2020 ◽  
Vol 34 ◽  
pp. 205873842097630
Author(s):  
Li Jiang ◽  
Mengmeng Zhang ◽  
Sixue Wang ◽  
Yuzhen Xiao ◽  
Jingni Wu ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Kegg Pathway ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Protein Protein Interaction ◽  
Cerna Network ◽  
Non Coding Rna ◽  
Differentially Expressed Mirnas ◽  
Long Non Coding Rna

The current study intended to explore the interaction of the long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) under the background of competitive endogenous RNA (ceRNA) network in endometriosis (EMs). The differentially expressed miRNAs (DEmiRs), differentially expressed lncRNA (DELs), and differentially expressed genes (DEGs) between EMs ectopic (EC) and eutopic (EU) endometrium based on three RNA-sequencing datasets (GSE105765, GSE121406, and GSE105764) were identified, which were used for the construction of ceRNA network. Then, DEGs in the ceRNA network were performed with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) analysis. Besides, the DEmiRs in the ceRNA network were validated in GSE124010. And the target DELs and DEGs of verified DEmiRs were validated in GSE86534. The correlation of verified DEmiRs, DEGs, and DELs was explored. Moreover, gene set enrichment analysis (GSEA) was applied to investigate the function of verified DEmiRs, DEGs, and DELs. Overall, 1352 DEGs and 595 DELs from GSE105764, along with 27 overlapped DEmiRs between GSE105765 and GSE121406, were obtained. Subsequently, a ceRNA network, including 11 upregulated and 16 downregulated DEmiRs, 7 upregulated and 13 downregulated DELs, 48 upregulated and 46 downregulated DEGs, was constructed. The GO and KEGG pathway analysis showed that this ceRNA network probably was associated with inflammation-related pathways. Furthermore, hsa-miR-182-5p and its target DELs (LINC01018 and SMIM25) and DEGs (BNC2, CHL1, HMCN1, PRDM16) were successfully verified in the validation analysis. Besides, hsa-miR-182-5p was significantly negatively correlated with these target DELs and DEGs. The GSEA analysis implied that high expression of LINC01018, SMIM25, and CHL1, and low expression of hsa-miR-182-5p would activate inflammation-related pathways in endometriosis EU samples. LINC01018 and SMIM25 might sponge hsa-miR-182-5p to upregulate downstream genes such as CHL1 to promote the development of endometriosis.

scholarly journals Differentially expressed genes in the femur cartilage transcriptome clarify the understanding of femoral head separation in chickens

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ludmila Mudri Hul ◽  
Adriana Mércia Guaratini Ibelli ◽  
Igor Ricardo Savoldi ◽  
Débora Ester Petry Marcelino ◽  
Lana Teixeira Fernandes ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Femoral Head ◽  
Transcriptome Analysis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Economic Losses ◽  
Rna Seq ◽  
Cellular Activation ◽  
Bone Anomalies

AbstractLocomotor problems are among one of the main concerns in the current poultry industry, causing major economic losses and affecting animal welfare. The most common bone anomalies in the femur are dyschondroplasia, femoral head separation (FHS), and bacterial chondronecrosis with osteomyelitis (BCO), also known as femoral head necrosis (FHN). The present study aimed to identify differentially expressed (DE) genes in the articular cartilage (AC) of normal and FHS-affected broilers by RNA-Seq analysis. In the transcriptome analysis, 12,169 genes were expressed in the femur AC. Of those, 107 genes were DE (FDR < 0.05) between normal and affected chickens, of which 9 were downregulated and 98 were upregulated in the affected broilers. In the gene-set enrichment analysis using the DE genes, 79 biological processes (BP) were identified and were grouped into 12 superclusters. The main BP found were involved in the response to biotic stimulus, gas transport, cellular activation, carbohydrate-derived catabolism, multi-organism regulation, immune system, muscle contraction, multi-organism process, cytolysis, leukocytes and cell adhesion. In this study, the first transcriptome analysis of the broilers femur articular cartilage was performed, and a set of candidate genes (AvBD1, AvBD2, ANK1, EPX, ADA, RHAG) that could trigger changes in the broiler´s femoral growth plate was identified. Moreover, these results could be helpful to better understand FHN in chickens and possibly in humans.

scholarly journals Paternal Obesity and SGLT2 Inhibition Alter Expression of Placental Regulatory Genes

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A752-A753
Author(s):  
Lei Su ◽  
Soravis Osataphan ◽  
Jessica Desmond ◽  
Rui Fang ◽  
Jeremy Chimene-Weiss ◽  
...  
Keyword(s):  
Sglt2 Inhibitor ◽  
Enrichment Analysis ◽  
Placental Weight ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Metabolic Effects ◽  
Altered Expression ◽  
Gene Sets ◽  
The Impact ◽  
Paternal Obesity

Abstract We previously demonstrated that paternal obesity is associated with offspring metabolic risk during later life, and that paternal SGLT2i treatment improves offspring metabolic phenotypes. Since the placenta is a key determinant of prenatal growth and development, we hypothesized the placenta could mediate the impact of paternal obesity and paternal SGLT2i treatment. Male C57BL/6J mice were fed standard chow (Purina 9F) or 60% high-fat diet (HFD, D12492, Research Diet), or 60% HFD plus the SGLT2 inhibitor canagliflozin (CANA, 25 mg/kg/d) for 4 weeks before mating with chow-fed females. Placenta were collected on E16.5, and RNA-seq was performed on placenta from male offspring (paternal chow, pChow, n=4, pHFD, n=5, and pHFD+CANA, n=4), and differentially expressed genes were identified using Limma. Placenta weight was significantly lower in pHFD (0.089±0.004 g, 7 litters from 6 fathers) vs. both pChow (0.108±0.011 g, 4 litters, 4 fathers) and pHFD+CANA (0.107±0.013 g, 5 litters, 5 fathers)(p&lt;0.05). Litter size, fetal or liver weight, or fetal/placental weight ratio did not differ between groups. No genes were differentially expressed in pHFD vs. pChow (FDR&lt;0.1). Gene set enrichment analysis (GSEA) identified significance (FDR&lt;0.05, NES&gt;1.8) for gene sets in steroid metabolic, drug catabolic, and protein-containing complex remodeling processes. Genes responsible for enrichment included cholesterol biosynthesis (Hmgcs1), transport (Apob, Apoa1/2/4, Apom, Apoc1, Vldlr, Pcsk9) and steroid hormone biosynthesis genes (Hsd3b1, Cyp11b1), all upregulated in pHFD by 1.5-3-fold. These results suggest pHFD could potentially affect maternal and fetal cholesterol homeostasis. pHFD+CANA altered expression of 154 genes vs. pHFD (7 up-, 147 down, FDR &lt;0.1, FC &gt;|1.5|); 18 gene sets were downregulated by pHFD+CANA (GSEA NES&lt;-1.8 and FDR&lt;0.05), including the 3 sets upregulated by pHFD. ChEA3 enrichment analysis (ENCODE library) predicted regulation by transcription factors important for cholesterol and sterol biosynthesis (Srebf1/2), embryonic development (Foxa2), & glucose homeostasis (Hnf4g), suggesting these pathways could mediate the “rescue” effect of pHFD+CANA (FDR&lt;0.05). Expression of Foxa2 was significantly downregulated (4-fold) in pHFD+CANA vs. pHFD. We independently analyzed expression of the 78 detected imprinted genes. None were significantly different in pHFD, but both paternally expressed (Nnat) and maternally expressed genes (H19, Phlda2, Meg3, Meg8) were downregulated in pHFD+CANA vs. pHFD by 1.4 to 3.8 fold in pHFD+CANA (p&lt;0.001,FDR&lt;0.1). In summary, paternal SGLT2i reversed the impact of pHFD on placental weight. Robust impact of both pHFD and pSGLT2i on the transcriptome suggests that the placenta is a key mediator of paternal metabolic effects on offspring development and metabolic disease risk, potentially via modification of lipid transport.

scholarly journals Blood and Brain Transcriptome Analysis Reveals APOE Genotype-mediated and Immune-related Pathways Involved in Alzheimer Disease

2021 ◽  
Author(s):  
Rebecca Panitch ◽  
Junming Hu ◽  
Weiming Xia ◽  
David A Bennett ◽  
Thor D Stein ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Blood Brain Barrier ◽  
Vascular Injury ◽  
Apoe Genotype ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Brain Barrier ◽  
Gene Set Enrichment ◽  
Gene Set

Abstract Background: While Alzheimer disease (AD) is generally considered as a brain disorder, blood biomarkers may be useful for diagnosis and prediction of AD brain pathology. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood brain barrier breakdown. Methods: We evaluated differential expression of previously established AD genes in brains from 344 pathologically confirmed AD cases and 232 controls and in blood from 112 pathologically confirmed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. Differential gene expression between AD cases and controls was analyzed in the blood and brain jointly using a multivariate approach in the total sample and within APOE genotype groups. Gene set enrichment analysis was performed within APOE genotype groups using the results from the combined blood and brain analyses to identify biologically important pathways. Gene co-expression networks in brain and blood samples were investigated using weighted correlation network analysis. Top ranked genes from networks and pathways were further evaluated with vascular injury traits. Results: We observed differentially expressed genes with P<0.05 in both brain and blood for established AD genes INPP5D (upregulated) and HLA-DQA1 (downregulated). PIGHP1 and FRAS1 were differentially expressed at the transcriptome-wide level (P<3.3x10 -6 ) within ε2/ε3 and ε3/ε4 groups, respectively. Gene-set enrichment analysis revealed 21 significant pathways (false discovery rate P<0.05) in at least one APOE genotype group. Ten pathways were significantly enriched in the ε3/ε4 group, and six of these were unique to these subjects. Four pathways were enriched for AD upregulated genes in the ε3/ε4 group and AD downregulated genes in ε4 lacking subjects. We identified a co-expressed gene network in brain that reproduced in blood and showed higher average expression in ε4 carriers. Twenty-three genes from pathway and network analyses were significantly associated at P<0.05 with at least one vascular injury trait. Conclusion: These results suggest that APOE genotype contributes to unique expression network profiles in both blood and brain. Several genes in these networks are associated with measures of vascular injury and potentially contribute to ε4’s effect on the blood brain barrier.

scholarly journals Expression Signatures of Long Noncoding RNAs in Left Ventricular Noncompaction

2021 ◽  
Vol 8 ◽  
Author(s):  
Qingshan Tian ◽  
Hanxiao Niu ◽  
Dingyang Liu ◽  
Na Ta ◽  
Qing Yang ◽  
...  
Keyword(s):  
Differentially Expressed Genes ◽  
Noncoding Rnas ◽  
Enrichment Analysis ◽  
Left Ventricular ◽  
Long Noncoding Rnas ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Control Group ◽  
Left Ventricular Noncompaction ◽  
Ventricular Noncompaction

Long noncoding RNAs have gained widespread attention in recent years for their crucial role in biological regulation. They have been implicated in a range of developmental processes and diseases including cancer, cardiovascular, and neuronal diseases. However, the role of long noncoding RNAs (lncRNAs) in left ventricular noncompaction (LVNC) has not been explored. In this study, we investigated the expression levels of lncRNAs in the blood of LVNC patients and healthy subjects to identify differentially expressed lncRNA that develop LVNC specific biomarkers and targets for developing therapies using biological pathways. We used Agilent Human lncRNA array that contains both updated lncRNAs and mRNAs probes. We identified 1,568 upregulated and 1,141 downregulated (log fold-change &gt; 2.0) lncRNAs that are differentially expressed between LVNC and the control group. Among them, RP11-1100L3.7 and XLOC_002730 are the most upregulated and downregulated lncRNAs. Using quantitative real-time reverse transcription polymerase chain reaction (RT-QPCR), we confirmed the differential expression of three top upregulated and downregulated lncRNAs along with two other randomly picked lncRNAs. Gene Ontology (GO) and KEGG pathways analysis with these differentially expressed lncRNAs provide insight into the cellular pathway leading to LVNC pathogenesis. We also identified 1,066 upregulated and 1,017 downregulated mRNAs. Gene set enrichment analysis (GSEA) showed that G2M, Estrogen, and inflammatory pathways are enriched in differentially expressed genes (DEG). We also identified miRNA targets for these differentially expressed genes. In this study, we first report the use of LncRNA microarray to understand the pathogenesis of LVNC and to identify several lncRNA and genes and their targets as potential biomarkers.

scholarly journals Understanding Heterogeneity of Fetal Hemoglobin Induction through Comparative Analysis of Stage-Matched F- and a-Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 981-981
Author(s):  
Eugene Khandros ◽  
Peng Huang ◽  
Scott A. Peslak ◽  
Belinda Giardine ◽  
Zhe Zhang ◽  
...  
Keyword(s):  
Research Funding ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Erythroid Cell ◽  
Alternative Mechanism ◽  
Globin Genes ◽  
A Cells ◽  
Hydroxyurea Treatment ◽  
F Cells

Reversing the developmental switch from fetal (HbF, α2γ2) to adult (HbA, α2β2) hemoglobin is an important therapeutic approach in sickle cell disease (SCD) and β-thalassemia. Elevated HbF levels due to genetic variation or through therapeutic induction by hydroxyurea (HU) attenuate the severity of both disorders. HbF in healthy individuals, SCD patients, and patients treated with HU is present in a heterocellular fashion in a subset of red blood cells known as F-cells. Despite over 50 years of observations of F-cells, it is not known why only some cells in a genetically identical population are able to express HbF or respond to pharmacological inducers. Adult F-cells can potentially represent a reversion to a fetal-like epigenetic and transcriptional program, or alternatively isolated transcriptional or posttranscriptional events at the γ-globin genes. Here we set out to understand the heterogeneity of HbF activation and gain insights into whether the mechanisms underlying the heterocellular response are similar or distinct in response to different HbF inducers. To this end we developed techniques to purify differentiation stage-matched late erythroblast F-cells and non-F cells (A-cells) from the human HUDEP2 erythroid cell line and primary CD34 cell erythroid cultures using a reversible fixation protocol enabling extraction of high-quality RNA and protein. Purified F-cells from both sources were enriched for γ-globin transcripts by 200-500 fold by RT-PCR, validating the purification scheme. We profiled these cells by RNA-seq using a modified method that depletes globin mRNAs and ribosomal RNAs and is capable of detecting low abundance transcripts, as well as by mass spectrometry using size fractionation to increase the number of detected proteins. In differentiated clonal HUDEP2 cells, differences between F-cells and A-cells were remarkably small, with only 62 differentially expressed transcripts and 20 differentially expressed proteins. Top differentially expressed transcripts were γ-globin and the non-coding β-globin locus transcripts BGLT3 and HBBP1. Interestingly, there were no significant changes in known HbF regulators BCL11A, LRF, and HRI at the RNA or protein level. Gene set enrichment analysis (GSEA) using a previously generated set of differentially expressed transcripts from adult and fetal-derived CD34 erythroid cultures showed enrichment of fetal transcripts in F-cells and adult transcripts in A-cells. We also carried out transcriptome analysis of sorted matched late erythroblast F-cells and A-cells from human CD34+ cell erythroid cultures at different time points. Similar to HUDEP2 cells, only small numbers of transcripts were differentially expressed (33 at 8 days, 17 at 11 days, and 261 at 14 days). BCL11A, LRF, and HRI were not differentially expressed at the earlier timepoints, and BCL11A and HRI were at most decreased by about 20% at the 14-day mark. GSEA analysis did not show fetal transcript enrichment in day 8. At days 11 and 14, there was some enrichment of fetal transcripts in F-cells but not to the degree of HUDEP2 cells. Finally, we analyzed sorted F- and A-cells from day 11 CD34+ erythroid cultures treated with hydroxyurea and pomalidomide. Again, differences between F- and A-cells were small with hydroxyurea treatment (53 transcripts) and more significant with pomalidomide treatment (400 transcripts). We have successfully established an approach to analyze stage-matched γ-globin containing cells from a genetically identical starting population, with high degree of enrichment. Our preliminary data indicate that these cells are overall highly similar to non-γ-containing cells, but do show some enrichment of fetal-specific transcripts, more so in HUDEP2 cells. The differences between F- and A- cells are overall smaller than those observed by us and others in profiling of fetal and adult-derived erythroblasts. This suggests that F-cells are not formed by reversion to a fetal-like state but rather through specific changes at the β-globin locus. Importantly, we do not find differential levels of any known γ-globin regulators, suggesting an alternative mechanism for the heterocellular expression pattern. Studies are currently ongoing to carry out epigenetic profiling of F-cells. Disclosures Blobel: Bioverativ: Research Funding; Pfizer: Research Funding.

Next Generation Sequencing reveals profound transcriptomic differences between reticulated and non-reticulated platelets from healthy donors, CCS- and STEMI patients

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Hille ◽  
T.G Nuehrenberg ◽  
L Hein ◽  
F.J Neumann ◽  
D Trenk
Keyword(s):  
Healthy Subjects ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Gene Set Enrichment ◽  
Reticulated Platelets ◽  
Gene Sets ◽  
Healthy Donors ◽  
Go Terms ◽  
Generation Sequencing

Abstract Background The youngest circulating platelets – so called reticulated platelets (RP) – represent a highly prothrombotic platelet subpopulation. Previous studies showed that patients with chronic coronary syndrome (CCS) as well as patients with ST-elevation myocardial infarction (STEMI) have higher amounts of RP compared to healthy subjects. It has been suggested that intrinsic properties of RP impact on cardiovascular risk. However, it is unknown if transcriptomic alterations contribute to the prothrombotic properties of RP. Purpose This study sought to investigate differences in the transcriptomic landscape of sorted RP versus non-RP, i.e. young and old platelets, in healthy subjects, CCS- and STEMI-patients. Methods Blood samples were obtained from healthy subjects as well as from patients with CCS/STEMI (n=8 each) the day after PCI. After staining with SYTO 13, platelets from each donor were sorted into a RP and a non-RP fraction based on their RNA-content. Next Generation Sequencing (NGS) was applied to generate sequencing reads for sorted RP and non-RP from the 3 cohorts. Data was analyzed by use of the Freiburg bioinformatics platform “Galaxy”. Results Investigation of transcriptomic alterations in non-RP versus RP by differential gene expression analysis revealed a total number of 2,476 transcripts that were differentially expressed in platelets from healthy donors, 2,075 in CCS-patients and 1,852 in STEMI patients, respectively (adj. p&lt;0.05 in all analyses). Comparison of these transcripts revealed a large overlap of 500 mRNAs which were downregulated and 660 mRNAs which were upregulated in RP in all 3 cohorts. However, there are also distinct groups of transcripts that are differentially expressed in only one of the 3 cohorts. Gene ontology (GO)-analysis of the 500 uniformly enriched transcripts in RP yielded 38 overrepresented GO-terms. A large group was related to cytoskeleton and shape change. Furthermore, GO-terms associated to the platelet activation cascade were overrepresented. Upregulated transcripts included well-known examples like GP6 and GP9, P-selectin, integrin β3, integrin a-IIb, and tubulin α4a. GO-analysis of enriched transcripts in non-RP showed a large group associated to mitosis and cell nucleus/DNA which is surprising since platelets neither contain DNA nor a nucleus. Gene set enrichment analysis (GSEA) determined higher normalized enrichment scores for several gene sets associated to platelet degranulation, aggregation and activation in the STEMI-cohort. Gene sets affecting cell adhesion and platelet calcium homeostasis were overexpressed in particular in CCS-patients. Conclusion NGS-results indicate a highly prothrombotic transcriptome of RP from each cohort with high amounts of differentially expressed transcripts overlapping. However, GSEA identified gene sets that are particularly overexpressed in CCS- or STEMI-patients which might contribute to platelet hyperreactivity in these cohorts. Gene set enrichment analysis Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): PharmCompNet Baden-Wuerttemberg: Kompetenznetzwerk Pharmakologie Baden-Wuerttemberg - Wirkstoffnetzwerke als Grundlagen der individualisierten Arzneistofftherapie

Oncogenic activation of the HRR pathway drives RAD54L expression in early stage lung adenocarcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20037-e20037
Author(s):  
Shaopeng Zheng ◽  
Jin Xia ◽  
Yunfang Yu ◽  
Fanjun Zeng ◽  
Luyu Huang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Survival Rate ◽  
Lung Adenocarcinoma ◽  
Early Stage ◽  
Enrichment Analysis ◽  
Tumor Stage ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Dna Damage And Repair ◽  
T1 Stage

e20037 Background: In recent years, there has been a better understanding of ways to use DNA damage and repair (DDR) mechanisms to improve overall sensitivity and/or overcome resistance to traditional DNA damage treatments. The DDR network is quite complex and highly dynamic with as many as 450 proteins integral to the DNA repair. The current study is to identify the key dysregulated genes and its related pathways especially DDR pathways in early progression of lung adenocarcinoma. Methods: TCGA dataset of lung adenocarcinoma (LUAD) including 59 healthy lung tissues and 517 tumor tissues was utilized to detect the differentially expressed mRNAs and lncRNAs. Gene ontology (GO) analysis was conducted with DAVID, while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes was performed using gene set enrichment analysis (GSEA) methods. Results: 41 lncRNAs and 2,047 mRNAs were screened out to be differentially expressed in LUAD. Besides, 38 lncRNAs and 1,801 mRNAs were found to be differentially expressed in T1 stage LUAD. The homologous recombination repair (HRR) pathway was found to be significantly up-regulated in LUAD, with four genes in this pathway up-regulated. In these genes of HRR pathway, PPP4R4 and RAD54L were recognized to be significantly differential expressed in T1 stage, compared with T2 stage and T3 stage, which were putative biomarkers of early stage LUAD. The survival analysis revealed that the expression of RAD54L was significantly related to the survival rate of patients with tumor of T1 stage. Conclusions: HRR pathway was up-regulated in lung adenocarcinoma, in which the expression of PPP4R4 and RAD54L were found to be tumor stage specific and RAD54L was related with survival rate of T1 stage patients. This study provided a further insight into the mechanism of the progression in early stage lung adenocarcinoma.

Integrated analysis of the expression, involved functions, and regulatory network of RUNX3 in melanoma

2021 ◽  
Vol 24 ◽  
Author(s):  
Yanxin Liu ◽  
Zhang Feng ◽  
Huaxia Chen
Keyword(s):  
Protein Interactions ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Integrated Analysis ◽  
Protein Protein Interactions ◽  
Nf Kappab ◽  
Microarray Datasets

Background: As a tumor suppressor or oncogenic gene, abnormal expression of RUNX family transcription factor 3 (RUNX3) has been reported in various cancers. Introduction: This study aimed to investigate the role of RUNX3 in melanoma. Methods: The expression level of RUNX3 in melanoma tissues was analyzed by immunohistochemistry and the Oncomine database. Based on microarray datasets GSE3189 and GSE7553, differentially expressed genes (DEGs) in melanoma samples were screened, followed by functional enrichment analysis. Gene Set Enrichment Analysis (GSEA) was performed for RUNX3. DEGs that co-expressed with RUNX3 were analyzed, and the transcription factors (TFs) of RUNX3 and its co-expressed genes were predicted. The protein-protein interactions (PPIs) for RUNX3 were analyzed utilizing the GeneMANIA database. MicroRNAs (miRNAs) that could target RUNX3 expression, were predicted. Results : RUNX3 expression was significantly up-regulated in melanoma tissues. GSEA showed that RUNX3 expression was positively correlated with melanogenesis and melanoma pathways. Eleven DEGs showed significant co-expression with RUNX3 in melanoma, for example, TLE4 was negatively co-expressed with RUNX3. RUNX3 was identified as a TF that regulated the expression of both itself and its co-expressed genes. PPI analysis showed that 20 protein-encoding genes interacted with RUNX3, among which 9 genes were differentially expressed in melanoma, such as CBFB and SMAD3. These genes were significantly enriched in transcriptional regulation by RUNX3, RUNX3 regulates BCL2L11 (BIM) transcription, regulation of I-kappaB kinase/NF-kappaB signaling, and signaling by NOTCH. A total of 31 miRNAs could target RUNX3, such as miR-326, miR-330-5p, and miR-373-3p. Conclusion: RUNX3 expression was up-regulated in melanoma and was implicated in the development of melanoma.

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