scholarly journals Exploring the impact of complex diseases on non-diseased human tissue transcriptomes

2021 ◽  
Author(s):  
Chi-Lam Poon ◽  
Cho-Yi Chen
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Human Body ◽  
Complex Disease ◽  
Association Studies ◽  
Genetic Effect ◽  
Complex Diseases ◽  
Functional Enrichment ◽  
The Impact

Abstract Background The development of complex diseases is contributed by the combination of multiple factors and complicated interactions between them. Inflammation has recently been associated with many complex diseases and may cause long-term damage to the human body. In this study, we examined whether two types of complex disease systematically altered the transcriptomes of non-diseased human tissues and whether inflammation was linked to identifiable molecular signatures, using post-mortem samples from the Genotype-Tissue Expression (GTEx) project. Results Following a series of differential expression (DE) analyses, dozens to hundreds of DE genes were identified in multiple tissues between subjects with and without a history of cerebrovascular disease (CVD) or major depression (MD). DE genes from these disease-associated tissues—the visceral adipose, tibial artery, caudate, and spinal cord for CVD; and the hypothalamus, putamen, and spinal cord for MD—were further analyzed for functional enrichment. Many pathways associated with immunological events were positively enriched in the DEGs of the CVD-associated tissues, as were the neurological and metabolic pathways in the MD-associated tissues. Eight gene–tissue pairs were found to overlap with those prioritized by our transcriptome-wide association studies (TWAS), indicating a potential genetic effect on gene expression for circulating cytokine phenotypes. Conclusions Complex diseases like CVD and MD may cause observable changes in the gene expression of non-diseased tissues, suggesting that a long-term impact of diseases, lifestyles and environmental factors may together contribute to the appearance of transcriptomic “scars” on the human body. Furthermore, inflammation is probably one of the systemic and long-lasting effects of cerebrovascular events.

scholarly journals Exploring the Impact of Cerebrovascular Disease and Major Depression on Non-diseased Human Tissue Transcriptomes

2021 ◽  
Vol 12 ◽  
Author(s):  
Chi-Lam Poon ◽  
Cho-Yi Chen
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Major Depression ◽  
Cerebrovascular Disease ◽  
Human Body ◽  
Association Studies ◽  
Complex Diseases ◽  
Functional Enrichment ◽  
The Impact

BackgroundThe development of complex diseases is contributed by the combination of multiple factors and complicated interactions between them. Inflammation has recently been associated with many complex diseases and may cause long-term damage to the human body. In this study, we examined whether two types of complex disease, cerebrovascular disease (CVD) or major depression (MD), systematically altered the transcriptomes of non-diseased human tissues and whether inflammation is linked to identifiable molecular signatures, using post-mortem samples from the Genotype-Tissue Expression (GTEx) project.ResultsFollowing a series of differential expression analyses, dozens to hundreds of differentially expressed genes (DEGs) were identified in multiple tissues between subjects with and without a history of CVD or MD. DEGs from these disease-associated tissues—the visceral adipose, tibial artery, caudate, and spinal cord for CVD; and the hypothalamus, putamen, and spinal cord for MD—were further analyzed for functional enrichment. Many pathways associated with immunological events were enriched in the upregulated DEGs of the CVD-associated tissues, as were the neurological and metabolic pathways in DEGs of the MD-associated tissues. Eight gene-tissue pairs were found to overlap with those prioritized by our transcriptome-wide association studies, indicating a potential genetic effect on gene expression for circulating cytokine phenotypes.ConclusionCerebrovascular disease and major depression cause detectable changes in the gene expression of non-diseased tissues, suggesting that a possible long-term impact of diseases, lifestyles and environmental factors may together contribute to the appearance of “transcriptomic scars” on the human body. Furthermore, inflammation is probably one of the systemic and long-lasting effects of cerebrovascular events.

scholarly journals TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 513
Author(s):  
Grace H. Yang ◽  
Danielle A. Fontaine ◽  
Sukanya Lodh ◽  
Joseph T. Blumer ◽  
Avtar Roopra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Association Studies ◽  
Cell Cycle Gene ◽  
Genome Wide Association Studies ◽  
Β Cell ◽  
Nucleotide Incorporation ◽  
Damage Response ◽  
The Impact

Transcription factor 19 (TCF19) is a gene associated with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that Tcf19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells and human islets on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNA-seq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in viral responses, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways can provide potential targets for improving β-cell survival.

scholarly journals Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis

2019 ◽  
Author(s):  
Jing Yang ◽  
Amanda McGovern ◽  
Paul Martin ◽  
Kate Duffus ◽  
Xiangyu Ge ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
T Cells ◽  
Complex Disease ◽  
Target Genes ◽  
Disease Risk ◽  
Association Studies ◽  
Dna Interaction ◽  
Genome Wide Association Studies ◽  
Causal Genes

AbstractGenome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T-cells over 24 hours, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T-cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.

scholarly journals The Impact of Long‐Term Physical Activity on Age‐Related Changes in Protein and Gene Expression

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Ian R Lanza ◽  
Daniel K Short ◽  
Kevin R Short ◽  
Yan W Asmann ◽  
Sreekumar Raghavakaimal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Physical Activity ◽  
Age Related ◽  
The Impact ◽  
Age Related Changes

184 CHANGES IN GENE EXPRESSION IS ASSOCIATED WITH SPINAL CORD LONG-TERM POTENTIATION

2006 ◽  
Vol 10 (S1) ◽  
pp. S50c-S50
Author(s):  
L.M. Jacobsen ◽  
L.M. Pedersen ◽  
J. Gjerstad
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Long Term Potentiation ◽  
Term Potentiation

Replicative Senescence-Associated Gene Expression Changes In Human MSPCs Independent of Genomic Variations

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4775-4775
Author(s):  
Katharina Schallmoser ◽  
Christina Bartmann ◽  
Eva Rohde ◽  
Simone Bork ◽  
Christian Guelly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Bone Marrow ◽  
Large Scale ◽  
Replicative Senescence ◽  
Genomic Stability ◽  
The State ◽  
Efficient Treatment ◽  
The Impact

Abstract Abstract 4775 Background: Based on promising experimental studies with mesenchymal stem and progenitor cells (MSPCs) multiple clinical trials have been initiated. In previous studies we have observed genomic stability of MSPCs after efficient short-term expansion in a humanized GMP compliant system with pooled human platelet lysate (pHPL) replacing fetal bovine serum (FBS) as the cell culture supplement (Schallmoser K. and Strunk D., Journal of Visualized Experiments (32) DOI: 10.3791/1523, 2009). Notably, depending on culture protocols, an extensive propagation with highly variable cell culture duration may be necessary to yield enough MSPCs for therapy. The decline in proliferation rates of MSPCs in the course of the different long-term expansion procedures may indicate a propensity for replicative senescence which may hamper long term functionality in vivo. We have therefore initiated a molecular profiling of senescence-associated regulated genes to determine the state of senescence before MSPC transplantation. Methods: Human bone marrow-derived MSPCs were cultured following a highly efficient two-passage protocol (primary culture of unseparated bone marrow and subsequent large scale expansion; Schallmoser K. et al., Tissue Engineering 14:185-196, 2008) compared to conventional serial passaging in three different growth conditions with regularly more then four passages to obtain comparable final cell numbers. Culture media were either supplemented with FBS in different concentrations or pHPL. Gene expression changes were tested by microarray analysis and selected targets were reanalyzed by quantitative real-time PCR. The genomic stability of MSPCs after long-term culture was determined by array comparative genomic hybridization (CGH). Results: Despite high proliferation rate large scale expanded MSPCs showed genomic stability in array CGH. Long-term MSPC growth induced similar gene expression changes in MSPCs irrespective of isolation and expansion conditions. In particular, genes involved in cell differentiation, apoptosis and cell death were up-regulated, whereas genes involved in mitosis and proliferation were down-regulated. Furthermore, overlapping senescence-associated gene expression changes were found in all MSPC preparations. The genomic copy number variations detected in MSPCs of early and late passages in all culture conditions did not coincide with differentially expressed genes. Conclusion: Our data indicate that MSPC expansion can induce gene expression changes independent of isolation and FBS-supplemented as well as FBS-free expansion conditions. A panel of genes will be presented that might offer a practicable approach to assess MSPC quality with regard to the state of replicative senescence in advance of therapeutic application. Determining the impact of senescence acquired during cell expansion on the therapeutic potential of MSCPs for both immune modulation and organ regeneration may help to develop more efficient treatment strategies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Uncovering complex disease subtypes by integrating clinical data and imputed transcriptome from genome-wide association studies: Applications in psychiatry and cardiovascular medicine

2019 ◽  
Author(s):  
Liangying Yin ◽  
Carlos K.L. Chau ◽  
Pak-Chung Sham ◽  
Hon-Cheong So
Keyword(s):  
Clinical Data ◽  
Complex Disease ◽  
Clinical Symptoms ◽  
Association Studies ◽  
Complex Diseases ◽  
Targeted Prevention ◽  
Genome Wide Association Studies ◽  
Biologically Relevant ◽  
Prediction Strength ◽  
Disease Subtypes

AbstractClassifying patients into clinically and biologically homogenous subgroups will facilitate the understanding of disease pathophysiology and development of more targeted prevention and intervention strategies. Traditionally, disease subtyping is based on clinical characteristics alone, however disease subtypes identified by such an approach may not conform exactly to the underlying biological mechanisms. Very few studies have integratedgenomic profiles(such as those from GWAS) with clinical symptoms for disease subtyping.In this study, we proposed a novel analytic framework capable of finding subgroups of complex diseases by leveraging both GWAS-predicted gene expression levels and clinical data by a multi-view bicluster analysis. This approach connects SNPs to genes via their effects on expression, hence the analysis is more biologically relevant and interpretable than a pure SNP-based analysis. Transcriptome of different tissues can also be readily modelled. We also proposed various new evaluation or validation metrics, such as a newly modified ‘prediction strength’ measure to assess generalization of clustering performance. The proposed framework was applied to derive subtypes for schizophrenia, and to stratify subjects into different levels of cardiometabolic risks.Our framework was able to subtype schizophrenia patients with diverse prognosis and treatment response. We also applied the framework to the Northern Finland Cohort (NFBC) 1966 dataset, and identified high- and low cardiometabolic risk subgroups in a gender-stratified analysis. Our results suggest a more data-driven and biologically-informed approach to defining metabolic syndrome. The prediction strength was over 80%, suggesting that the cluster model generalizes well to new datasets. Moreover, we found that the genes ‘blindly’ selected by the cluster algorithm are significantly enriched for known susceptibility genes discovered in GWAS of schizophrenia and cardiovascular diseases, providing further support to the validity of our approach. The proposed framework may be applied to any complex diseases, and opens up a new approach to patient stratification.

scholarly journals Persistence of rhombomeric organisation in the postsegmental hindbrain

Development ◽  
1996 ◽  
Vol 122 (7) ◽  
pp. 2143-2152 ◽  
Author(s):  
R.J. Wingate ◽  
A. Lumsden
Keyword(s):  
Gene Expression ◽  
Radial Glia ◽  
Ventricular Zone ◽  
In Situ Hybridisation ◽  
Proliferating Cells ◽  
Nuclear Organisation ◽  
Transverse Pattern ◽  
Marginal Zones ◽  
The Impact

Rhombomeres are morphological varicosities of the neural tube that are present between embryonic day (E) 1.5 and E5 and are characterised by compartment organisation, segmentally neuronal organisation and spatially restricted patterns of gene expression. After E5, the segmented origins of the hindbrain become indistinct, while the adult hindbrain has an longitudinal columnar nuclear organisation. In order to assess the impact of the early transverse pattern on later longitudinal organisation, we have used orthotopic quail grafts and in situ hybridisation to investigate the long-term fate of rhombomeres in the embryonic chick hindbrain. The uniformity of mixing between quail and chick cells was first verified using short-term aggregation cultures. The dispersal of the progeny of individual rhombomeres (r) was then assessed by the unilateral, isochronic and orthotopic transplantation of either r2, r3, r4, r5 or r6 from quail to chick at embryonic day E2. In addition, orthotopic, partial rhombomere grafts, encompassing an inter-rhombomere boundary and adjacent rhombomere bodies were used to assess cell mixing within rhombomeres. Operated embryos were incubated to either E7 or E10 when chimaeric brains were removed. Quail cells were identified in whole mounts or serial sections using the quail-specific antibody QCPN. Subsequently, radial glia morphology was assessed either by immunohistochemistry or DiI labelling. A series of fixed hindbrains between E6 and E9 were probed for transcripts of Hoxa-2 and Hoxb-1. Fate-mapping reveals that the progeny of individual rhombomeres form stripes of cells running dorsoventrally through the hindbrain. This pattern of dispersal precisely parallels the array of radial glia. Although the postmitotic progeny of adjacent rhombomeres spread to some extent into each others' territory in intermediate and marginal zones, there is little or no mixing between rhombomeres in the ventricular zone, which thus remains compartmentalised long after the rhombomeric morphology disappears. Segmental gene expression within this layer is also maintained after E5. A more detailed analysis of mixing between proliferating cells, using partial rhombomere grafts, reveals that both mixing and growth are non-uniform within the ventricular layer, suggesting, in particular, that longitudinal expansion within this layer is restricted. Together, these observations suggest that rhombomeres do not disappear at E5, as has previously been supposed, rather they persist in the ventricular zone to at least E9, ensuring a continuity in the presumed segmental cues that specify neuroepithelial cells in the hindbrain.

scholarly journals Co-expression analysis reveals interpretable gene modules controlled by trans-acting genetic variants

2020 ◽  
Author(s):  
Liis Kolberg ◽  
Nurlan Kerimov ◽  
Hedi Peterson ◽  
Kaur Alasoo
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Expression Analysis ◽  
Complex Disease ◽  
Target Genes ◽  
Disease Onset ◽  
Functional Enrichment ◽  
Eqtl Analysis ◽  
Cell Type ◽  
Motif Analysis

AbstractBackgroundDeveloping novel therapies for complex disease requires better understanding of the causal processes that contribute to disease onset and progression. Although trans-acting gene expression quantitative trait loci (trans-eQTLs) can be a powerful approach to directly reveal cellular processes modulated by disease variants, detecting trans-eQTLs remains challenging due to their small effect sizes and large number of genes tested. However, if a single trans-eQTL controls a group of co-regulated genes, then multiple testing burden can be greatly reduced by summarising gene expression at the level of co-expression modules prior to trans-eQTL analysis.ResultsWe analysed gene expression and genotype data from six blood cell types from 226 to 710 individuals. We inferred gene co-expression modules with five methods on the full dataset, as well as in each cell type separately. We detected a number of established co-expression module trans-eQTLs, such as the monocyte-specific associations at the IFNB1 and LYZ loci, as well as a platelet-specific ARHGEF3 locus associated with mean platelet volume. We also discovered a novel trans association near the SLC39A8 gene in LPS-stimulated monocytes. Here, we linked an early-response cis-eQTL of the SLC39A8 gene to a module of co-expressed metallothionein genes upregulated more than 20 hours later and used motif analysis to identify zinc-induced activation of the MTF1 transcription factor as a likely mediator of this effect.ConclusionsOur analysis provides a rare detailed characterisation of a trans-eQTL effect cascade from a proximal cis effect to the affected signalling pathway, transcription factor, and target genes. This highlights how co-expression analysis combined with functional enrichment analysis can greatly improve the identification and prioritisation of trans-eQTLs when applied to emerging cell-type specific datasets.

scholarly journals Deep inspiration breath hold versus free breathing technique in mediastinal radiotherapy for lymphoma

BJR|Open ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 20200067
Author(s):  
Orla Anne Houlihan ◽  
Guhan Rangaswamy ◽  
Mary Dunne ◽  
Christine Rohan ◽  
Louise O'Neill ◽  
...  
Keyword(s):  
Spinal Cord ◽  
At Risk ◽  
Clinical Practice ◽  
Organs At Risk ◽  
Free Breathing ◽  
Breath Hold ◽  
Deep Inspiration ◽  
Deep Inspiration Breath Hold ◽  
The Impact

Objective: Radiotherapy plays an important role in the management of lymphoma and many patients with lymphoma are cured with treatment. Risk of secondary malignancy and long-term cardiac and pulmonary toxicity from mediastinal radiotherapy exists. Delivery of radiotherapy using a deep inspiration breath-hold (DIBH) technique increases lung volume and has the potential to reduce dose to heart and lungs. We undertook a prospective study to assess the dosimetric differences in DIBH and free breathing (FB) plans in patients requiring mediastinal radiotherapy in clinical practice. Methods: We performed both FB and DIBH planning scans on 35 consecutive patients with mediastinal lymphoma needing radiotherapy. Contours and plans were generated for both data sets and dosimetric data were compared. All patients were planned using volumetric modulated arc therapy (VMAT). Data were compared for FB and DIBH plans with each patient acting as their own control using the related-samples Wilcoxon signed rank test. Results: DIBH significantly reduced lung doses (mean 10.6 vs 11.4Gy, p < 0.0005; V20 16.8 vs 18.3%, p = 0.001) and spinal cord maximum dose (20.6 vs 22.8Gy, p = 0.001). DIBH increased breast V4 (38.5% vs 31.8%, p = 0.006) and mean right breast dose (4.2 vs 3.6Gy, p = 0.010). There was no significant difference in heart doses when the entire study cohort was considered, however, mean heart dose tended to be lower with DIBH for upper mediastinal (UM) tumours (4.3 vs 4.9Gy, p = 0.05). Conclusion: Our study describes the potential benefit of DIBH in a population reflective of clinical practice. DIBH can decrease radiation dose to lungs, heart and spinal cord, however, may increase dose to breasts. DIBH is not always superior to FB, and the clinical significance of differences in dose to organs at risk in addition to the time required to treat patients with DIBH must be considered when deciding the most appropriate radiotherapy technique for each patient. Advances in knowledge: To our knowledge, this is the largest study comparing DIBH and FB planning for patients with lymphoma receiving mediastinal radiotherapy in clinical practice. It demonstrates the impact of an increasingly common radiotherapy technique on dose to organs at risk and the subsequent potential for long-term radiotherapy side-effects.

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