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Towards a deeper understanding of the human brain
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.ORCID iD: 0000-0002-0327-7377
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Identifying the proteome variation in different parts of the body provides fundamental molecular details, enabling further findings and mapping of tissue specific proteins. By combining quantitative transcriptomics with qualitative antibody based proteomics, the Human Protein Atlas (HPA) project aims to protein profile each human protein-coding gene. Genes with varying expression levels in the different tissue types are categorized as tissue elevated in one tissue compared to others, thus connecting genes to potential tissue specific functions. This thesis focuses on the most complex organ in the human body, the brain. With its billions of neurons specifically organized and interconnected, the ability of not only controlling the body but also responsible for higher cognitive functions, the brain is still not fully understood.

In my search for brain important proteins, genes were classified at different stages based on expression levels. In Paper I and II the transcriptome of cerebral cortex was compared with peripheral organs to classify genes with elevated expression in the brain. Brain expression information was expanded by including external data (GTEx and FANTOM5) into the analysis, in Paper III. Thereafter, in Paper IV, the three datasets (HPA, GTEx and FANTOM5) were aligned and combined, enabling a consensus classification with an improved representation of the brain complexity. The most recent classification provided whole body gene expression profiles and out of the 19,670 protein-coding genes, 2,501 were expressed at elevated levels in the brain compared to the other tissue types. Twelve individual regions represented the brain as an organ, and were further analyzed and compared for regional classification of gene expression. One thousand genes showed regional variation in expression level, thus classified as regionally elevated within the brain. Interestingly, less than 500 of the genes classified as brain elevated on the whole body level, and were also regionally elevated in the brain. Many genes with regionally variable expression within the brain showed higher expression in a peripheral organ than in the brain when comparing whole body expression. Based on elevated expression in the brain or brain regions, more than 3,000 genes were suggested to be of high importance to the brain.

In addition, this high-throughput approach to combine transcriptomics and protein profiles in tissues and cells further generated new knowledge in several different other aspects: better understanding of uncharacterized and “missing proteins” (Paper III), validation of an antibody improving classification of pituitary adenoma (Paper V) and in Paper VI the possibility to explore cancer specific expression in relation to clinical data and normal tissue expression.

There are multiple diseases of the brain that are poorly understood on both a cellular and molecular level. While my work mainly focused on identifying and understanding the molecular organization of the normal brain, the ultimate goal of mapping and studying the normal expression baseline is to understand the molecular aspects of disease and identify ways to prevent, treat and cure diseases.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2018. , p. 83
Series
TRITA-CBH-FOU ; 50
Keywords [en]
Brain, organization, RNA, classification, mapping, proteins, antibodies
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-235670ISBN: 978-91-7729-983-7 (print)OAI: oai:DiVA.org:kth-235670DiVA, id: diva2:1256615
Public defence
2018-11-15, Gard aulan, Nobels väg 18, Solna, 10:00 (English)
Opponent
Supervisors
Note

QC 20181018

Available from: 2018-10-18 Created: 2018-10-17 Last updated: 2018-10-18Bibliographically approved
List of papers
1. Tissue-based map of the human proteome
Open this publication in new window or tab >>Tissue-based map of the human proteome
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2015 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, no 6220, p. 1260419-Article in journal (Refereed) Published
Abstract [en]

Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.

Keywords
isoprotein, membrane protein, protein, proteome, tumor protein
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-160035 (URN)10.1126/science.1260419 (DOI)000348225800036 ()25613900 (PubMedID)2-s2.0-84925582323 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg Foundation
Note

QC 20150216

Available from: 2015-02-13 Created: 2015-02-13 Last updated: 2018-10-17Bibliographically approved
2. Defining the Human Brain Proteome Using Transcriptomics and Antibody-Based Profiling with a Focus on the Cerebral Cortex
Open this publication in new window or tab >>Defining the Human Brain Proteome Using Transcriptomics and Antibody-Based Profiling with a Focus on the Cerebral Cortex
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id UNSP e0130028Article in journal (Refereed) Published
Abstract [en]

The mammalian brain is a complex organ composed of many specialized cells, harboring sets of both common, widely distributed, as well as specialized and discretely localized proteins. Here we focus on the human brain, utilizing transcriptomics and public available Human Protein Atlas (HPA) data to analyze brain-enriched (frontal cortex) polyadenylated messenger RNA and long non-coding RNA and generate a genome-wide draft of global and cellular expression patterns of the brain. Based on transcriptomics analysis of altogether 27 tissues, we have estimated that approximately 3% (n=571) of all protein coding genes and 13% (n=87) of the long non-coding genes expressed in the human brain are enriched, having at least five times higher expression levels in brain as compared to any of the other analyzed peripheral tissues. Based on gene ontology analysis and detailed annotation using antibody-based tissue micro array analysis of the corresponding proteins, we found the majority of brain-enriched protein coding genes to be expressed in astrocytes, oligodendrocytes or in neurons with molecular properties linked to synaptic transmission and brain development. Detailed analysis of the transcripts and the genetic landscape of brainenriched coding and non-coding genes revealed brain-enriched splice variants. Several clusters of neighboring brain-enriched genes were also identified, suggesting regulation of gene expression on the chromatin level. This multi-angle approach uncovered the brainenriched transcriptome and linked genes to cell types and functions, providing novel insights into the molecular foundation of this highly specialized organ.

National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-170972 (URN)10.1371/journal.pone.0130028 (DOI)000356329900125 ()26076492 (PubMedID)
Note

QC 20150713

Available from: 2015-07-13 Created: 2015-07-13 Last updated: 2018-10-17Bibliographically approved
3. Integration of Transcriptomics and Antibody-Based Proteomics for Exploration of Proteins Expressed in Specialized Tissues
Open this publication in new window or tab >>Integration of Transcriptomics and Antibody-Based Proteomics for Exploration of Proteins Expressed in Specialized Tissues
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2018 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 17, no 12, p. 4127-4137Article in journal (Refereed) Published
Abstract [en]

A large portion of human proteins are referred to as missing proteins, defined as protein-coding genes that lack experimental data on the protein level due to factors such as temporal expression, expression in tissues that are difficult to sample, or they actually do not encode functional proteins. In the present investigation, an integrated omics approach was used for identification and exploration of missing proteins. Transcriptomics data from three different sourcesthe Human Protein Atlas (HPA), the GTEx consortium, and the FANTOM5 consortiumwere used as a starting point to identify genes selectively expressed in specialized tissues. Complementing the analysis with profiling on more specific tissues based on immunohistochemistry allowed for further exploration of cell-type-specific expression patterns. More detailed tissue profiling was performed for >300 genes on complementing tissues. The analysis identified tissue-specific expression of nine proteins previously listed as missing proteins (POU4F1, FRMD1, ARHGEF33, GABRG1, KRTAP2-1, BHLHE22, SPRR4, AVPR1B, and DCLK3), as well as numerous proteins with evidence of existence on the protein level that previously lacked information on spatial resolution and cell-type- specific expression pattern. We here present a comprehensive strategy for identification of missing proteins by combining transcriptomics with antibody-based proteomics. The analyzed proteins provide interesting targets for organ-specific research in health and disease.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
missing proteins, transcriptomics, proteomics, protein localization, immunohistochemistry, antibodies, tissue profiling
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Biological Sciences
Research subject
Biotechnology
Identifiers
urn:nbn:se:kth:diva-236474 (URN)10.1021/acs.jproteome.8b00406 (DOI)000452930000010 ()30272454 (PubMedID)2-s2.0-85055105364 (Scopus ID)
Note

QC 20181018

Available from: 2018-10-17 Created: 2018-10-17 Last updated: 2019-01-11Bibliographically approved
4. The transcriptomic landscape of mammalian brain
Open this publication in new window or tab >>The transcriptomic landscape of mammalian brain
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences Medical Biotechnology
Research subject
Biotechnology; Medical Technology
Identifiers
urn:nbn:se:kth:diva-236079 (URN)
Note

QC 20181018

Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2018-10-18Bibliographically approved
5. A specific antibody to detect transcription factor T-Pit: a reliable marker of corticotroph cell differentiation and a tool to improve the classification of pituitary neuroendocrine tumours
Open this publication in new window or tab >>A specific antibody to detect transcription factor T-Pit: a reliable marker of corticotroph cell differentiation and a tool to improve the classification of pituitary neuroendocrine tumours
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2017 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 134, no 4, p. 675-677Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
SPRINGER, 2017
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-214869 (URN)10.1007/s00401-017-1768-9 (DOI)000409369000012 ()2-s2.0-85027889508 (Scopus ID)
Note

QC 20171024

Available from: 2017-10-24 Created: 2017-10-24 Last updated: 2018-10-17Bibliographically approved
6. A pathology atlas of the human cancer transcriptome
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 ()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: 2018-10-17Bibliographically approved

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