Biology subjects

Odeberg, J.

Publications and source records attributed to Odeberg, J..

7 recordsLinked to original sources

bioRxiv2023

Temporal transcriptome analysis of the endothelial response to tumour necrosis factor

The vascular endothelium acts as a dynamic interface between blood and tissue and provides an anti-inflammatory and anti-thrombotic surface under normal conditions. Tumour necrosis factor- (TNF), a cytokine that drives acute and chronic inflammation, induces numerous transcriptional changes in endothelial cells (EC). However, the overall temporal dynamics of this response have not been fully elucidated. Here, we conducted an extended time-course analysis of the EC response to TNF, from 30 minutes to 72 hours. We identified TNF-regulated genes and used weighted gene correlation network analysis (WGCNA) to decipher co-expression profiles, uncovering two distinct temporal phases - an acute response initiated between 1-4 hours, followed by a later phase initiated between 12-24 hours. Several previously uncharacterised genes were strongly regulated during the acute phase, while the majority in the later phase were interferon-stimulated genes (ISGs). A lack of interferon transcription indicated that this TNF-induced ISG expression was independent of de novo interferon production and autocrine signalling. Furthermore, we observed two different groups of genes whose transcription was inhibited by TNF, those that resolved towards baseline levels over time, and those that did not. Our study provides insights into the global temporal dynamics of the EC transcriptional response to TNF, highlighting distinct gene expression patterns during the acute and later phases. These findings may be useful in understanding the role of EC in inflammation and developing TNF signalling-targeting therapies.

cell biology↗

bioRxiv2023

A human stomach cell type transcriptome atlas

The identification of cell type-specific genes and their modification under different conditions is central to our understanding of human health and disease. The stomach, a hollow organ in the upper gastrointestinal tract, provides an acidic environment that contributes to microbial defence and facilitates the activity of secreted digestive enzymes to process food and nutrients into chyme. In contrast to other sections of the gastrointestinal tract, detailed descriptions of cell type gene enrichment profiles in the stomach are absent from the major single cell sequencing-based atlases. Here, we use an integrative correlation analysis method to predict human stomach cell type transcriptome signatures using unfractionated stomach RNAseq data from 359 individuals. We profile parietal, chief, gastric mucous, gastric enteroendocrine, mitotic, endothelial, fibroblast, macrophage, neutrophil, T-cell and plasma cells, identifying over 1600 cell type-enriched genes. We uncover the cell type expression profile of several non-coding genes strongly associated with the progression of gastric cancer and, using a sex-based subset analysis, uncover a panel of male-only chief cell-enriched genes. This study provides a roadmap to further understand human stomach biology.

systems biology↗

bioRxiv2023

A tissue centric atlas of cell type transcriptome enrichment signatures

Genes with cell type specific expression typically encode for proteins that have cell type specific functions. Single cell RNAseq (scRNAseq) has facilitated the identification of such genes, but various challenges limit the analysis of certain cell types and lowly expressed genes. Here, we performed an integrative network analysis of over 6000 bulk RNAseq datasets from 15 human organs, to generate a tissue-by-tissue cell type enrichment prediction atlas for all protein coding genes. We profile all the major constituent cell types, including several that are fragile or difficult to process and thus absent from existing scRNAseq-based atlases. The stability and read depth of bulk RNAseq data, and the high number of biological replicates analysed, allowed us to identify lowly expressed cell type enriched genes that are difficult to classify using existing methods. We identify co-enriched gene panels shared by pancreatic alpha and beta cells, chart temporal changes in cell enrichment signatures during spermatogenesis, and reveal that cells in the hair root are a major source of skin enriched genes. In a cross-tissue analysis, we identify shared gene enrichment signatures between highly metabolic and motile cell types, and core identity profiles of cell types found in across tissue types. Our study provides the only cell type gene enrichment atlas generated independently of scRNAseq, representing a new addition to our existing toolbox of resources for the understanding of gene expression across human tissues.

systems biology↗

bioRxiv2021

Testing for association with rare variants in the coding and non-coding genome: RAVA-FIRST, a new approach based on CADD deleteriousness score

Rare variant association tests (RVAT) have been developed to study the contribution of rare variants widely accessible through high-throughput sequencing technologies. RVAT require to aggregate rare variants in testing units and to filter variants to retain only the most likely causal ones. In the exome, genes are natural testing units and variants are usually filtered based on their functional consequences. However, when dealing with whole-genome sequence (WGS) data, both steps are challenging. No natural biological unit is available for aggregating rare variants. Sliding windows procedures have been proposed to circumvent this difficulty, however they are blind to biological information and result in a large number of tests. We propose a new strategy to perform RVAT on WGS data: "RAVA-FIRST" (RAre Variant Association using Functionally-InfoRmed STeps) comprising three steps. (1) New testing units are defined genome-wide based on functionally-adjusted Combined Annotation Dependent Depletion (CADD) scores of variants observed in the GnomAD populations, which are referred to as "CADD regions". (2) A region-dependent filtering of rare variants is applied in each CADD region. (3) A functionally-informed burden test is performed with sub-scores computed for each genomic category within each CADD region. Both on simulations and real data, RAVA-FIRST was found to outperform other WGS-based RVAT. Applied to a WGS dataset of venous thromboembolism patients, we identified an intergenic region on chromosome 18 that is enriched for rare variants in early-onset patients and that was that was missed by standard sliding windows procedures. RAVA-FIRST enables new investigations of rare non-coding variants in complex diseases, facilitated by its implementation in the R package Ravages. Author SummaryTechnological progresses have made possible whole genome sequencing at an unprecedented scale, opening up the possibility to explore the role of genetic variants of low frequency in common diseases. The challenge is now methodological and requires the development of novel methods and strategies to analyse sequencing data that are not limited to assessing the role of coding variants. With RAVA-FIRST, we propose a novel strategy to investigate the role of rare variants in the whole-genome that takes benefit from biological information. Especially, RAVA-FIRST relies on testing units that go beyond genes to gather rare variants in the association tests. In this work, we show that this new strategy presents several advantages compared to existing methods. RAVA-FIRST offers an easy and straightforward analysis of genome-wide rare variants, especially the intergenic ones which are frequently left behind, making it a promising tool to get a better understanding of the biology of complex diseases.

genetics↗

bioRxiv2020

Facets of individual-specific health signatures determined from longitudinal plasma proteome profiling

BackgroundPrecision medicine approaches aim to tackle diseases on an individual level through molecular profiling. Despite the growing knowledge about diseases and the reported diversity of molecular phenotypes, the descriptions of human health on an individual level have been far less elaborate. MethodsTo provide insights into the longitudinal protein signatures of well-being, we profiled blood plasma collected over one year from 101 clinically healthy individuals using multiplexed antibody assays. After applying an antibody validation scheme, we utilized > 700 protein profiles for in-depth analyses of the individuals short-term health trajectories. FindingsWe found signatures of circulating proteomes to be highly individual-specific. Considering technical and longitudinal variability, we observed both stable and fluctuating proteins in the circulation, as well as networks of proteins that covaried over time. For each participant, there were unique protein profiles and some of these could be explained by associations to genetic variants. InterpretationThis study demonstrates that there was noticeable diversity among clinically healthy subjects, and facets of individual-specific signatures emerged by monitoring the variability of the circulating proteomes over time. Longitudinal profiling of circulating proteomes has the potential to enable a more personal hence precise assessment of health states, and thereby provide a valuable component of precision medicine approaches. FundingThis work was supported by the Erling Persson Foundation for the KTH Centre for Precision Medicine and the Swedish Heart and Lung Foundation for the SCAPIS project. We also acknowledge the Knut and Alice Wallenberg Foundation for funding the Human Protein Atlas project, Science for Life Laboratory for Plasma Profiling Facility, and the Swedish Research Council (Grant no 2017-00641).

biochemistry↗

bioRxiv2019

A systems-based map of human brain cell-type enriched genes and malignancy-associated endothelial changes

Changes in the endothelium of the cerebral vasculature can contribute to inflammatory, thrombotic and malignant disorders. The importance of defining cell type-specific genes and how they are modified in disease is increasingly recognised. Here, we developed a bioinformatics-based approach to identify normal brain cell-enriched genes, using bulk RNAseq data from 238 normal human cortex samples from 2 independent cohorts. We compared endothelial cell-enriched gene profiles with astrocyte, oligodendrocyte and neuron profiles. Global modifications to the endothelium in malignant disease were characterised, using RNAseq data from 516 human lower grade gliomas and 401 human glioblastoma multiforme samples. Lower grade glioma appeared to be an endothelial intermediate between normal brain and glioblastoma multiforme. We identify the most highly glioblastoma multiforme-specific endothelial cell biomarkers, providing potential diagnostic or therapeutic targets. In summary, we provide a roadmap of endothelial cell identity in normal and malignant brain tissue, using a bioinformatics-based method developed to resolve bulk RNAseq datasets into constituent cell type-enriched profiles.

cell biology↗

bioRxiv2018

Levels of histidine-rich glycoprotein in human blood predict accelerated aging

1.Despite recognizing aging as risk factor of human diseases, little is still known about the molecular traits of biological age and mortality risk. To identify age-associated proteins circulating human blood, we screened 156 subjects aged 50-92 years using an exploratory and multiplexed affinity proteomics approach. We corroborated the top age-associated protein profile (adjusted P < 0.001) in eight additional study sets (N = 4,044 individuals), and confirmed a consistent age-associated increase (P = 6.61 x 10-6) by meta-analysis. Applying antibody validation determined circulating histidine-rich glycoprotein (HRG) as the target, and we observed that sequence variants influenced the antibodies ability to bind to the protein. Profiles of circulating HRG were associated to several clinical traits and predicted the risk of mortality during a follow-up period of 8.5 years (IQR = 7.7-9.3 years) after blood sampling (HR = 1.25 per SD; 95% CI = 1.12-1.39; P = 7.41 x 10-5). In conclusion, our affinity proteomics analysis found associations between the molecular traits of circulating HRG with age and all-cause mortality. This suggests that the profiles of multi-purpose protein HRG could serve as an accessible indicator of physiological processes related to aging.

epidemiology↗