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Uhlén, M., Karlsson, M., Zhong, W., Abdellah, T., Pou, C., Mikes, J., . . . Brodin, P. (2019). A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science, 366(6472), 1471-+, Article ID eaax9198.
Open this publication in new window or tab >>A genome-wide transcriptomic analysis of protein-coding genes in human blood cells
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2019 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 366, no 6472, p. 1471-+, article id eaax9198Article in journal (Refereed) Published
Abstract [en]

Blood is the predominant source for molecular analyses in humans, both in clinical and research settings. It is the target for many therapeutic strategies, emphasizing the need for comprehensive molecular maps of the cells constituting human blood. In this study, we performed a genome-wide transcriptomic analysis of protein-coding genes in sorted blood immune cell populations to characterize the expression levels of each individual gene across the blood cell types. All data are presented in an interactive, open-access Blood Atlas as part of the Human Protein Atlas and are integrated with expression profiles across all major tissues to provide spatial classification of all protein-coding genes. This allows for a genome-wide exploration of the expression profiles across human immune cell populations and all major human tissues and organs.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2019
National Category
Genetics
Identifiers
urn:nbn:se:kth:diva-266527 (URN)10.1126/science.aax9198 (DOI)000503861000045 ()31857451 (PubMedID)2-s2.0-85077091174 (Scopus ID)
Note

QC 20200205

Available from: 2020-02-05 Created: 2020-02-05 Last updated: 2020-03-02Bibliographically approved
Pineau, C., Hikmet, F., Zhang, C., Oksvold, P., Chen, S., Fagerberg, L., . . . Lindskog, C. (2019). Cell Type-Specific Expression of Testis Elevated Genes Based on Transcriptomics and Antibody-Based Proteomics. Journal of Proteome Research, 18(12), 4215-4230
Open this publication in new window or tab >>Cell Type-Specific Expression of Testis Elevated Genes Based on Transcriptomics and Antibody-Based Proteomics
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2019 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 18, no 12, p. 4215-4230Article in journal (Refereed) Published
Abstract [en]

One of the most complex organs in the human body is the testis, where spermatogenesis takes place. This physiological process involves thousands of genes and proteins that are activated and repressed, making testis the organ with the highest number of tissue-specific genes. However, the function of a large proportion of the corresponding proteins remains unknown and testis harbors many missing proteins (MPs), defined as products of protein-coding genes that lack experimental mass spectrometry evidence. Here, an integrated omics approach was used for exploring the cell type-specific protein expression of genes with an elevated expression in testis. By combining genome-wide transcriptomics analysis with immunohistochemistry, more than 500 proteins with distinct testicular protein expression patterns were identified, and these were selected for in-depth characterization of their in situ expression in eight different testicular cell types. The cell type-specific protein expression patterns allowed us to identify six distinct clusters of expression at different stages of spermatogenesis. The analysis highlighted numerous poorly characterized proteins in each of these clusters whose expression overlapped with that of known proteins involved in spermatogenesis, including 88 proteins with an unknown function and 60 proteins that previously have been classified as MPs. Furthermore, we were able to characterize the in situ distribution of several proteins that previously lacked spatial information and cell type-specific expression within the testis. The testis elevated expression levels both at the RNA and protein levels suggest that these proteins are related to testis-specific functions. In summary, the study demonstrates the power of combining genome-wide transcriptomics analysis with antibody-based protein profiling to explore the cell type-specific expression of both well-known proteins and MPs. The analyzed proteins constitute important targets for further testis-specific research in male reproductive disorders.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
Keywords
antibody-based proteomics, immunohistochemistry, missing proteins, protein evidence, reproduction, spermatogenesis, testis, transcriptomics
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-263250 (URN)10.1021/acs.jproteome.9b00351 (DOI)000502164100015 ()31429579 (PubMedID)2-s2.0-85072574178 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20191106

Available from: 2019-11-06 Created: 2019-11-06 Last updated: 2020-03-09Bibliographically approved
Neiman, M., Hellström, C., Just, D., Mattsson, C., Fagerberg, L., Schuppe-Koistinen, I., . . . Nilsson, P. (2019). Individual and stable autoantibody repertoires in healthy individuals. Autoimmunity, 52(1), 1-11
Open this publication in new window or tab >>Individual and stable autoantibody repertoires in healthy individuals
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2019 (English)In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 52, no 1, p. 1-11Article in journal (Refereed) Published
Abstract [en]

In the era towards precision medicine, we here present the individual specific autoantibody signatures of 193 healthy individuals. The self-reactive IgG signatures are stable over time in a way that each individual profile is recognized in longitudinal sampling. The IgG autoantibody reactivity towards an antigen array comprising 335 protein fragments, representing 204 human proteins with potential relevance to autoimmune disorders, was measured in longitudinal plasma samples from 193 healthy individuals. This analysis resulted in unique autoantibody barcodes for each individual that were maintained over one year's time. The reactivity profiles, or signatures, are person specific in regards to the number of reactivities and antigen specificity. Two independent data sets were consistent in that each healthy individual displayed reactivity towards 0-16 antigens, with a median of six. Subsequently, four selected individuals were profiled on in-house produced high-density protein arrays containing 23,000 protein fragments representing 14,000 unique protein coding genes. Based on a unique, broad and deep longitudinal profiling of autoantibody reactivities, our results demonstrate a unique autoreactive profile in each analyzed healthy individual. The need and interest for broad-ranged and high-resolution molecular profiling of healthy individuals is rising. We have here generated and assessed an initial perspective on the global distribution of the self-reactive IgG repertoire in healthy individuals, by investigating 193 well-characterized healthy individuals.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2019
Keywords
Autoantibody repertoire, autoantibody profile, protein array, affinity proteomics, precision medicine
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-249825 (URN)10.1080/08916934.2019.1581774 (DOI)000462921100001 ()30835561 (PubMedID)2-s2.0-85062520789 (Scopus ID)
Note

QC 20190423

Available from: 2019-04-23 Created: 2019-04-23 Last updated: 2020-01-10Bibliographically approved
Häussler, R. S., Bendes, A., Iglesias, M. J., Sanchez-Rivera, L., Dodig-Crnkovic, T., Byström, S., . . . Schwenk, J. M. (2019). Systematic Development of Sandwich Immunoassays for the Plasma Secretome. Proteomics, Article ID 1900008.
Open this publication in new window or tab >>Systematic Development of Sandwich Immunoassays for the Plasma Secretome
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2019 (English)In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, article id 1900008Article in journal (Refereed) Published
Abstract [en]

The plasma proteome offers a clinically useful window into human health. Recent advances from highly multiplexed assays now call for appropriate pipelines to validate individual candidates. Here, a workflow is developed to build dual binder sandwich immunoassays (SIA) and for proteins predicted to be secreted into plasma. Utilizing suspension bead arrays, ≈1800 unique antibody pairs are first screened against 209 proteins with recombinant proteins as well as EDTA plasma. Employing 624 unique antibodies, dilution-dependent curves in plasma and concentration-dependent curves of full-length proteins for 102 (49%) of the targets are obtained. For 22 protein assays, the longitudinal, interindividual, and technical performance is determined in a set of plasma samples collected from 18 healthy subjects every third month over 1 year. Finally, 14 of these assays are compared with with SIAs composed of other binders, proximity extension assays, and affinity-free targeted mass spectrometry. The workflow provides a multiplexed approach to screen for SIA pairs that suggests using at least three antibodies per target. This design is applicable for a wider range of targets of the plasma proteome, and the assays can be applied for discovery but also to validate emerging candidates derived from other platforms.

Place, publisher, year, edition, pages
Wiley, 2019
Keywords
antibodies, plasma, sandwich assays, screening, secreted proteins
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-255741 (URN)10.1002/pmic.201900008 (DOI)000477448900001 ()31278833 (PubMedID)2-s2.0-85069914143 (Scopus ID)
Note

QC 20190812

Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2020-01-10Bibliographically approved
Uhlén, M., Karlsson, M. J., Hober, A., Svensson, A.-S., Scheffel, J., Kotol, D., . . . Sivertsson, Å. (2019). The human secretome. Science Signaling, 12(609), Article ID eaaz0274.
Open this publication in new window or tab >>The human secretome
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2019 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 12, no 609, article id eaaz0274Article in journal (Refereed) Published
Abstract [en]

The proteins secreted by human cells (collectively referred to as the secretome) are important not only for the basic understanding of human biology but also for the identification of potential targets for future diagnostics and therapies. Here, we present a comprehensive analysis of proteins predicted to be secreted in human cells, which provides information about their final localization in the human body, including the proteins actively secreted to peripheral blood. The analysis suggests that a large number of the proteins of the secretome are not secreted out of the cell, but instead are retained intracellularly, whereas another large group of proteins were identified that are predicted to be retained locally at the tissue of expression and not secreted into the blood. Proteins detected in the human blood by mass spectrometry-based proteomics and antibody-based immuno-assays are also presented with estimates of their concentrations in the blood. The results are presented in an updated version 19 of the Human Protein Atlas in which each gene encoding a secretome protein is annotated to provide an open-access knowledge resource of the human secretome, including body-wide expression data, spatial localization data down to the single-cell and subcellular levels, and data about the presence of proteins that are detectable in the blood.

Place, publisher, year, edition, pages
NLM (Medline), 2019
National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:kth:diva-265462 (URN)10.1126/scisignal.aaz0274 (DOI)000499099300003 ()31772123 (PubMedID)2-s2.0-85075677906 (Scopus ID)
Note

QC 20191218

Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2020-01-10Bibliographically approved
Dusart, P., Fagerberg, L., Perisic, L., Civelek, M., Struck, E., Hedin, U., . . . Butler, L. . (2018). A systems-approach reveals human nestin is an endothelial-enriched, angiogenesis-independent intermediate filament protein. Scientific Reports, 8(1), Article ID 14668.
Open this publication in new window or tab >>A systems-approach reveals human nestin is an endothelial-enriched, angiogenesis-independent intermediate filament protein
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 14668Article in journal (Refereed) Published
Abstract [en]

The intermediate filament protein nestin is expressed during embryonic development, but considered largely restricted to areas of regeneration in the adult. Here, we perform a body-wide transcriptome and protein-profiling analysis to reveal that nestin is constitutively, and highly-selectively, expressed in adult human endothelial cells (EC), independent of proliferative status. Correspondingly, we demonstrate that it is not a marker for tumour EC in multiple malignancy types. Imaging of EC from different vascular beds reveals nestin subcellular distribution is shear-modulated. siRNA inhibition of nestin increases EC proliferation, and nestin expression is reduced in atherosclerotic plaque neovessels. eQTL analysis reveals an association between SNPs linked to cardiovascular disease and reduced aortic EC nestin mRNA expression. Our study challenges the dogma that nestin is a marker of proliferation, and provides insight into its regulation and function in EC. Furthermore, our systems-based approach can be applied to investigate body-wide expression profiles of any candidate protein. 

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-236564 (URN)10.1038/s41598-018-32859-4 (DOI)000446034000069 ()30279450 (PubMedID)2-s2.0-85054173189 (Scopus ID)
Note

Export Date: 22 October 2018; Article; Correspondence Address: Butler, L.M.; Science for Life Laboratory, School of Biotechnology, Kungliga Tekniska Högskolan (KTH) Royal Institute of TechnologySweden; email: Lynn.Butler@ki.se. QC 20181127

Available from: 2018-11-27 Created: 2018-11-27 Last updated: 2020-03-09Bibliographically approved
Edfors, F., Hober, A., Linderbäck, K., Maddalo, G., Azimi, A., Sivertsson, Å., . . . Uhlén, M. (2018). Enhanced validation of antibodies for research applications. Nature Communications, 9, Article ID 4130.
Open this publication in new window or tab >>Enhanced validation of antibodies for research applications
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 4130Article in journal (Refereed) Published
Abstract [en]

There is a need for standardized validation methods for antibody specificity and selectivity. Recently, five alternative validation pillars were proposed to explore the specificity of research antibodies using methods with no need for prior knowledge about the protein target. Here, we show that these principles can be used in a streamlined manner for enhanced validation of research antibodies in Western blot applications. More than 6,000 antibodies were validated with at least one of these strategies involving orthogonal methods, genetic knockdown, recombinant expression, independent antibodies, and capture mass spectrometry analysis. The results show a path forward for efforts to validate antibodies in an application-specific manner suitable for both providers and users.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:kth:diva-237096 (URN)10.1038/s41467-018-06642-y (DOI)000446566000016 ()30297845 (PubMedID)2-s2.0-85054574300 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg Foundation
Note

QC 20181030

Available from: 2018-10-30 Created: 2018-10-30 Last updated: 2020-01-10Bibliographically approved
Uhlén, M., Zhang, C., Lee, S., Sjöstedt, E., Fagerberg, L., Bidkhori, G., . . . Ponten, F. (2017). A pathology atlas of the human cancer transcriptome. Science, 357(6352), 660-+
Open this publication in new window or tab >>A pathology atlas of the human cancer transcriptome
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2017 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 357, no 6352, p. 660-+Article in journal (Refereed) Published
Abstract [en]

Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open-access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2017
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-214334 (URN)10.1126/science.aan2507 (DOI)000407793600028 ()28818916 (PubMedID)2-s2.0-85028362951 (Scopus ID)
Funder
Swedish Cancer SocietyScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg FoundationSwedish Research Council
Note

QC 20170913

Available from: 2017-09-13 Created: 2017-09-13 Last updated: 2020-03-09Bibliographically approved
Thul, P. J., Åkesson, L., Wiking, M., Mahdessian, D., Geladaki, A., Ait Blal, H., . . . Lundberg, E. (2017). A subcellular map of the human proteome. Science, 356(6340), Article ID 820.
Open this publication in new window or tab >>A subcellular map of the human proteome
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2017 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 356, no 6340, article id 820Article in journal (Refereed) Published
Abstract [en]

Resolving the spatial distribution of the human proteome at a subcellular level can greatly increase our understanding of human biology and disease. Here we present a comprehensive image-based map of subcellular protein distribution, the Cell Atlas, built by integrating transcriptomics and antibody-based immunofluorescence microscopy with validation by mass spectrometry. Mapping the in situ localization of 12,003 human proteins at a single-cell level to 30 subcellular structures enabled the definition of the proteomes of 13 major organelles. Exploration of the proteomes revealed single-cell variations in abundance or spatial distribution and localization of about half of the proteins to multiple compartments. This subcellular map can be used to refine existing protein-protein interaction networks and provides an important resource to deconvolute the highly complex architecture of the human cell.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2017
Keywords
antibody, proteome, biology, cells and cell components, disease incidence, image analysis, physiological response, protein, proteomics, spatial distribution, Article, cell organelle, cellular distribution, human, human cell, immunofluorescence microscopy, mass spectrometry, priority journal, protein analysis, protein localization, protein protein interaction, single cell analysis, transcriptomics
National Category
Cell Biology
Identifiers
urn:nbn:se:kth:diva-216588 (URN)10.1126/science.aal3321 (DOI)000401957900032 ()28495876 (PubMedID)2-s2.0-85019201137 (Scopus ID)
Note

QC 20171208

Available from: 2017-12-08 Created: 2017-12-08 Last updated: 2020-03-09Bibliographically approved
Butler, L. M., Hallström, B. M., Fagerberg, L., Pontén, F., Uhlén, M., Renné, T. & Odeberg, J. (2016). Analysis of Body-wide Unfractionated Tissue Data to Identify a Core Human Endothelial Transcriptome. Cell Systems, 3(3), 287-301.e3
Open this publication in new window or tab >>Analysis of Body-wide Unfractionated Tissue Data to Identify a Core Human Endothelial Transcriptome
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2016 (English)In: Cell Systems, ISSN 2405-4712, Vol. 3, no 3, p. 287-301.e3Article in journal (Refereed) Published
Abstract [en]

Endothelial cells line blood vessels and regulate hemostasis, inflammation, and blood pressure. Proteins critical for these specialized functions tend to be predominantly expressed in endothelial cells across vascular beds. Here, we present a systems approach to identify a panel of human endothelial-enriched genes using global, body-wide transcriptomics data from 124 tissue samples from 32 organs. We identified known and unknown endothelial-enriched gene transcripts and used antibody-based profiling to confirm expression across vascular beds. The majority of identified transcripts could be detected in cultured endothelial cells from various vascular beds, and we observed maintenance of relative expression in early passage cells. In summary, we describe a widely applicable method to determine cell-type-specific transcriptome profiles in a whole-organism context, based on differential abundance across tissues. We identify potential vascular drug targets or endothelial biomarkers and highlight candidates for functional studies to increase understanding of the endothelium in health and disease.

Place, publisher, year, edition, pages
Cell Press, 2016
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-202878 (URN)10.1016/j.cels.2016.08.001 (DOI)000395775300011 ()27641958 (PubMedID)2-s2.0-84991734935 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20170310

Available from: 2017-03-10 Created: 2017-03-10 Last updated: 2020-03-09Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0198-7137

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