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Robinson, J. L., Kocabas, P., Wang, H., Cholley, P.-E., Cook, D., Nilsson, A., . . . Nielsen, J. (2020). An atlas of human metabolism. Science Signaling, 13(624), Article ID eaaz1482.
Open this publication in new window or tab >>An atlas of human metabolism
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2020 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 13, no 624, article id eaaz1482Article in journal (Refereed) Published
Abstract [en]

Genome-scale metabolic models (GEMs) are valuable tools to study metabolism and provide a scaffold for the integrative analysis of omics data. Researchers have developed increasingly comprehensive human GEMs, but the disconnect among different model sources and versions impedes further progress. We therefore integrated and extensively curated the most recent human metabolic models to construct a consensus GEM, Human1. We demonstrated the versatility of Human1 through the generation and analysis of cell- and tissue-specific models using transcriptomic, proteomic, and kinetic data. We also present an accompanying web portal, Metabolic Atlas (https://www.metabolicatlas.org/), which facilitates further exploration and visualization of Human1 content. Human1 was created using a version-controlled, open-source model development framework to enable community-driven curation and refinement. This framework allows Human1 to be an evolving shared resource for future studies of human health and disease.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2020
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-271928 (URN)10.1126/scisignal.aaz1482 (DOI)000521753000003 ()32209698 (PubMedID)2-s2.0-85082380687 (Scopus ID)
Note

QC 20200421

Available from: 2020-04-21 Created: 2020-04-21 Last updated: 2020-04-21Bibliographically approved
Sjöstedt, E., Zhong, W., Fagerberg, L., Karlsson, M., Mitsios, N., Adori, C., . . . Mulder, J. (2020). An atlas of the protein-coding genes in the human, pig, and mouse brain. Science, 367(6482), 1090-+, Article ID eaay5947.
Open this publication in new window or tab >>An atlas of the protein-coding genes in the human, pig, and mouse brain
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2020 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 367, no 6482, p. 1090-+, article id eaay5947Article in journal (Refereed) Published
Abstract [en]

The brain, with its diverse physiology and intricate cellular organization, is the most complex organ of the mammalian body. To expand our basic understanding of the neurobiology of the brain and its diseases, we performed a comprehensive molecular dissection of 10 major brain regions and multiple subregions using a variety of transcriptomics methods and antibody-based mapping. This analysis was carried out in the human, pig, and mouse brain to allow the identification of regional expression profiles, as well as to study similarities and differences in expression levels between the three species. The resulting data have been made available in an open-access Brain Atlas resource, part of the Human Protein Atlas, to allow exploration and comparison of the expression of individual protein-coding genes in various parts of the mammalian brain.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2020
National Category
Medical Genetics
Identifiers
urn:nbn:se:kth:diva-271745 (URN)10.1126/science.aay5947 (DOI)000520018400034 ()32054698 (PubMedID)2-s2.0-85081532587 (Scopus ID)
Note

QC 20200408

Available from: 2020-04-08 Created: 2020-04-08 Last updated: 2020-04-08Bibliographically approved
Li, X., Turanli, B., Juszczak, K., Kim, W., Arif, M., Sato, Y., . . . Mardinoglu, A. (2020). Classification of clear cell renal cell carcinoma based on PKM alternative splicing. Heliyon, 6(2), Article ID e03440.
Open this publication in new window or tab >>Classification of clear cell renal cell carcinoma based on PKM alternative splicing
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2020 (English)In: Heliyon, ISSN 2405-8440, Vol. 6, no 2, article id e03440Article in journal (Refereed) Published
Abstract [en]

Clear cell renal cell carcinoma (ccRCC) accounts for 70-80% of kidney cancer diagnoses and displays high molecular and histologic heterogeneity. Hence, it is necessary to reveal the underlying molecular mechanisms involved in progression of ccRCC to better stratify the patients and design effective treatment strategies. Here, we analyzed the survival outcome of ccRCC patients as a consequence of the differential expression of four transcript isoforms of the pyruvate kinase muscle type (PKM). We first extracted a classification biomarker consisting of eight gene pairs whose within-sample relative expression orderings (REOs) could be used to robustly classify the patients into two groups with distinct molecular characteristics and survival outcomes. Next, we validated our findings in a validation cohort and an independent Japanese ccRCC cohort. We finally performed drug repositioning analysis based on transcriptomic expression profiles of drug-perturbed cancer cell lines and proposed that paracetamol, nizatidine, dimethadione and conessine can be repurposed to treat the patients in one of the subtype of ccRCC whereas chenodeoxycholic acid, fenoterol and hexylcaine can be repurposed to treat the patients in the other subtype.

Place, publisher, year, edition, pages
Elsevier, 2020
Keywords
Bioinformatics, Cancer research, Systems biology, PKM, Alternative splicing, Transcriptomics, Biomarker, Drug repositioning
National Category
Clinical Medicine
Identifiers
urn:nbn:se:kth:diva-271527 (URN)10.1016/j.heliyon.2020.e03440 (DOI)000518367800131 ()32095654 (PubMedID)2-s2.0-85079659277 (Scopus ID)
Note

QC 20200427

Available from: 2020-04-27 Created: 2020-04-27 Last updated: 2020-04-27Bibliographically approved
Lyu, C., Lyu, G.-W., Mulder, J., Uhlén, M., Cai, X.-H., Hokfelt, T. & Shi, T.-J. S. (2020). Expression and regulation of FRMD6 in mouse DRG neurons and spinal cord after nerve injury. Scientific Reports, 10(1), Article ID 1880.
Open this publication in new window or tab >>Expression and regulation of FRMD6 in mouse DRG neurons and spinal cord after nerve injury
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2020 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 10, no 1, article id 1880Article in journal (Refereed) Published
Abstract [en]

FRMD6, a member of the group of FERM-domain proteins, is involved both in communication between cells, interactions with extracellular matrix, cellular apoptotic and regenerative mechanisms. FRMD6 was first discovered in the rodent sciatic nerve, and in the present immunohistochemical study we investigated the distribution of FRMD6 in the dorsal root ganglia (DRGs), sciatic nerve and spinal cord following sciatic nerve injury. FRMD6-immunoreactivity was found in the cytoplasm, nucleus or both, and in a majority of DRG neurons. FRMD6-immunoreactivity co-existed with several well-known neuronal markers, including calcitonin gene-related peptide, isolectin B4 and neurofilament 200 in mouse DRGs. After peripheral nerve injury, the FRMD6 mRNA levels and the overall percentage of FRMD6-positive neuron profiles (NPs) were decreased in ipsilateral lumbar DRGs, the latter mainly affecting small size neurons with cytoplasmic localization. Conversely, the proportion of NPs with nuclear FRMD6-immunoreactivity was significantly increased. In the sciatic nerve, FRMD6-immunoreactivity was observed in non-neuronal cells and in axons, and accumulated proximally to a ligation of the nerve. In the spinal cord FRMD6-immunoreactivity was detected in neurons in both dorsal and ventral horns, and was upregulated in ipsilateral dorsal horn after peripheral nerve axotomy. Our results demonstrate that FRMD6 is strictly regulated by peripheral nerve injury at the spinal level.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2020
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-270909 (URN)10.1038/s41598-020-58261-7 (DOI)000515602400001 ()32024965 (PubMedID)2-s2.0-85079060043 (Scopus ID)
Note

QC 20200324

Available from: 2020-03-24 Created: 2020-03-24 Last updated: 2020-03-24Bibliographically approved
Wang, D., Eraslan, B., Wieland, T., Hallström, B. M., Hopf, T., Zolg, D. P., . . . Kuster, B. (2019). A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Molecular Systems Biology, 15(2), Article ID e8503.
Open this publication in new window or tab >>A deep proteome and transcriptome abundance atlas of 29 healthy human tissues
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2019 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 15, no 2, article id e8503Article in journal (Refereed) Published
Abstract [en]

Genome-, transcriptome- and proteome-wide measurements provide insights into how biological systems are regulated. However, fundamental aspects relating to which human proteins exist, where they are expressed and in which quantities are not fully understood. Therefore, we generated a quantitative proteome and transcriptome abundance atlas of 29 paired healthy human tissues from the Human Protein Atlas project representing human genes by 18,072 transcripts and 13,640 proteins including 37 without prior protein-level evidence. The analysis revealed that hundreds of proteins, particularly in testis, could not be detected even for highly expressed mRNAs, that few proteins show tissue-specific expression, that strong differences between mRNA and protein quantities within and across tissues exist and that protein expression is often more stable across tissues than that of transcripts. Only 238 of 9,848 amino acid variants found by exome sequencing could be confidently detected at the protein level showing that proteogenomics remains challenging, needs better computational methods and requires rigorous validation. Many uses of this resource can be envisaged including the study of gene/protein expression regulation and biomarker specificity evaluation.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
human proteome, human transcriptome, proteogenomics, quantitative mass spectrometry, RNA-Seq
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-246279 (URN)10.15252/msb.20188503 (DOI)000459628300002 ()30777892 (PubMedID)2-s2.0-85061866375 (Scopus ID)
Note

QC 20190325

Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2020-01-10Bibliographically approved
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
Robinson, J. L., Feizi, A., Uhlén, M. & Nielsen, J. (2019). A Systematic Investigation of the Malignant Functions and Diagnostic Potential of the Cancer Secretome. Cell reports, 26(10), 2622-+
Open this publication in new window or tab >>A Systematic Investigation of the Malignant Functions and Diagnostic Potential of the Cancer Secretome
2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 26, no 10, p. 2622-+Article in journal (Refereed) Published
Abstract [en]

The collection of proteins secreted from a cell-the secretome-is of particular interest in cancer pathophysiology due to its diagnostic potential and role in tumorigenesis. However, cancer secretome studies are often limited to one tissue or cancer type or focus on biomarker prediction without exploring the associated functions. We therefore conducted a pan-cancer analysis of secretome gene expression changes to identify candidate diagnostic biomarkers and to investigate the underlying biological function of these changes. Using transcriptomic data spanning 32 cancer types and 30 healthy tissues, we quantified the relative diagnostic potential of secretome proteins for each cancer. Furthermore, we offer a potential mechanism by which cancer cells relieve secretory pathway stress by decreasing the expression of tissue-specific genes, thereby facilitating the secretion of proteins promoting invasion and proliferation. These results provide a more systematic understanding of the cancer secretome, facilitating its use in diagnostics and its targeting for therapeutic development.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:kth:diva-246230 (URN)10.1016/j.celrep.2019.02.025 (DOI)000460280800010 ()30840886 (PubMedID)2-s2.0-85061659881 (Scopus ID)
Note

QC 20190404

Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2020-01-10Bibliographically approved
Dusart, P., Hallström, B. M., Renne, T., Odeberg, J., Uhlén, M. & Butler, L. M. (2019). A Systems-Based Map of Human Brain Cell-Type Enriched Genes and Malignancy-Associated Endothelial Changes. Cell reports, 29(6), 1690-+
Open this publication in new window or tab >>A Systems-Based Map of Human Brain Cell-Type Enriched Genes and Malignancy-Associated Endothelial Changes
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 29, no 6, p. 1690-+Article in journal (Refereed) Published
Abstract [en]

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 their modification in disease is increasingly recognized. Here, we develop a bioinformatics-based approach to identify normal brain cell-enriched genes, using bulk RNA sequencing (RNA-seq) data from 238 normal human cortex samples from 2 independent cohorts. We compare endothelial cell-enriched gene profiles with astrocyte, oligodendrocyte, neuron, and microglial cell profiles. Endothelial changes in malignant disease are explored using RNA-seq data from 516 lower-grade gliomas and 401 glioblastomas. Lower-grade gliomas appear to be an "endothelial intermediate'' between normal brain and glioblastoma. We apply our method for the prediction of glioblastoma-specific endothelial biomarkers, providing potential diagnostic or therapeutic targets. In summary, we provide a roadmap of endothelial cell identity in normal and malignant brain, using a method developed to resolve bulk RNA-seq into constituent cell-type-enriched profiles.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Clinical Medicine
Identifiers
urn:nbn:se:kth:diva-264333 (URN)10.1016/j.celrep.2019.09.088 (DOI)000495045400024 ()31693905 (PubMedID)2-s2.0-85074281897 (Scopus ID)
Note

QC 20191126. QC 20200109

Available from: 2019-11-26 Created: 2019-11-26 Last updated: 2020-01-10Bibliographically approved
Hober, A., Edfors, F., Ryaboshapkina, M., Malmqvist, J., Rosengren, L., Percy, A. J., . . . Miliotis, T. (2019). Absolute Quantification of Apolipoproteins Following Treatment with Omega-3 Carboxylic Acids and Fenofibrate Using a High Precision Stable Isotope-labeled Recombinant Protein Fragments Based SRM Assay. Molecular & Cellular Proteomics, 18(12), 2433-2446
Open this publication in new window or tab >>Absolute Quantification of Apolipoproteins Following Treatment with Omega-3 Carboxylic Acids and Fenofibrate Using a High Precision Stable Isotope-labeled Recombinant Protein Fragments Based SRM Assay
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2019 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 12, p. 2433-2446Article in journal (Refereed) Published
Abstract [en]

Stable isotope-labeled standard (SIS) peptides are used as internal standards in targeted proteomics to provide robust protein quantification, which is required in clinical settings. However, SIS peptides are typically added post trypsin digestion and, as the digestion efficiency can vary significantly between peptides within a protein, the accuracy and precision of the assay may be compromised. These drawbacks can be remedied by a new class of internal standards introduced by the Human Protein Atlas project, which are based on SIS recombinant protein fragments called SIS PrESTs. SIS PrESTs are added initially to the sample and SIS peptides are released on trypsin digestion. The SIS PrEST technology is promising for absolute quantification of protein biomarkers but has not previously been evaluated in a clinical setting. An automated and scalable solid phase extraction workflow for desalting and enrichment of plasma digests was established enabling simultaneous preparation of up to 96 samples. Robust high-precision quantification of 13 apolipoproteins was achieved using a novel multiplex SIS PrEST-based LC-SRM/MS Tier 2 assay in non-depleted human plasma. The assay exhibited inter-day coefficients of variation between 1.5% and 14.5% (median = 3.5%) and was subsequently used to investigate the effects of omega-3 carboxylic acids (OM3-CA) and fenofibrate on these 13 apolipoproteins in human plasma samples from a randomized placebo-controlled trial, EFFECT I (NCT02354976). No significant changes were observed in the OM3-CA arm, whereas treatment with fenofibrate significantly increased apoAII and reduced apoB, apoCI, apoE and apoCIV levels. The reduction in apoCIV following fenofibrate treatment is a novel finding. The study demonstrates that SIS PrESTs can facilitate the generation of robust multiplexed biomarker Tier 2 assays for absolute quantification of proteins in clinical studies. Applications of LC-SRM in clinical research are still limited. SIS PrEST are a novel class of standards added prior to trypsinization. We have developed a semi-automated sample preparation workflow and a SIS PrEST LC-SRM/MS Tier 2 assay for absolute quantification of 13 apolipoproteins in human plasma and applied it on clinical samples from the EFFECT I study. We demonstrate, for the first time, that SIS PrEST can be applied for exploratory biomarker research in clinical settings and capture drug effects.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2019
Keywords
Clinical trials, assay development, targeted mass spectrometry, selected reaction monitoring, absolute quantification, apolipoproteins, fenofibrate and omega-3 carboxylic acids, NAFLD, SIS PrEST
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-266286 (URN)10.1074/mcp.RA119.001765 (DOI)000501288700007 ()31591263 (PubMedID)2-s2.0-85075958078 (Scopus ID)
Note

QC 20200108

Available from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-01-10Bibliographically 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
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8993-048X

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