Change search
Link to record
Permanent link

Direct link
BETA
Nielsen, Jens
Publications (10 of 21) Show all publications
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: 2019-04-04Bibliographically approved
Hu, Y., Zhu, Z., Nielsen, J. & Siewers, V. (2018). Heterologous transporter expression for improved fatty alcohol secretion in yeast. Metabolic engineering, 45, 51-58
Open this publication in new window or tab >>Heterologous transporter expression for improved fatty alcohol secretion in yeast
2018 (English)In: Metabolic engineering, ISSN 1096-7176, E-ISSN 1096-7184, Vol. 45, p. 51-58Article in journal (Refereed) Published
Abstract [en]

The yeast Saccharomyces cerevisiae is an attractive host for industrial scale production of biofuels including fatty alcohols due to its robustness and tolerance towards harsh fermentation conditions. Many metabolic engineering strategies have been applied to generate high fatty alcohol production strains. However, impaired growth caused by fatty alcohol accumulation and high cost of extraction are factors limiting large-scale production. Here, we demonstrate that the use of heterologous transporters is a promising strategy to increase fatty alcohol production. Among several plant and mammalian transporters tested, human FATP1 was shown to mediate fatty alcohol export in a high fatty alcohol production yeast strain. An approximately five-fold increase of fatty alcohol secretion was achieved. The results indicate that the overall cell fitness benefited from fatty alcohol secretion and that the acyl-CoA synthase activity of FATP1 contributed to increased cell growth as well. This is the first study that enabled an increased cell fitness for fatty alcohol production by heterologous transporter expression in yeast, and this investigation indicates a new potential function of FATP1, which has been known as a free fatty acid importer to date. We furthermore successfully identified the functional domain of FATP1 involved in fatty alcohol export through domain exchange between FATP1 and another transporter, FATP4. This study may facilitate a successful commercialization of fatty alcohol production in yeast and inspire the design of novel cell factories.

Place, publisher, year, edition, pages
Academic Press, 2018
National Category
Biocatalysis and Enzyme Technology
Identifiers
urn:nbn:se:kth:diva-219890 (URN)10.1016/j.ymben.2017.11.008 (DOI)000424292100006 ()2-s2.0-85036454456 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research EU, Horizon 2020, 720824Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20171215

Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2018-03-13Bibliographically approved
Mardinoglu, A., Boren, J., Smith, U., Uhlén, M. & Nielsen, J. (2018). Systems biology in hepatology: approaches and applications. Nature Reviews. Gastroenterology & Hepatology, 15(6), 365-377
Open this publication in new window or tab >>Systems biology in hepatology: approaches and applications
Show others...
2018 (English)In: Nature Reviews. Gastroenterology & Hepatology, ISSN 1759-5045, E-ISSN 1759-5053, Vol. 15, no 6, p. 365-377Article, review/survey (Refereed) Published
Abstract [en]

Detailed insights into the biological functions of the liver and an understanding of its crosstalk with other human tissues and the gut microbiota can be used to develop novel strategies for the prevention and treatment of liver-associated diseases, including fatty liver disease, cirrhosis, hepatocellular carcinoma and type 2 diabetes mellitus. Biological network models, including metabolic, transcriptional regulatory, protein-protein interaction, signalling and co-expression networks, can provide a scaffold for studying the biological pathways operating in the liver in connection with disease development in a systematic manner. Here, we review studies in which biological network models were used to integrate multiomics data to advance our understanding of the pathophysiological responses of complex liver diseases. We also discuss how this mechanistic approach can contribute to the discovery of potential biomarkers and novel drug targets, which might lead to the design of targeted and improved treatment strategies. Finally, we present a roadmap for the successful integration of models of the liver and other human tissues with the gut microbiota to simulate whole-body metabolic functions in health and disease.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:kth:diva-230482 (URN)10.1038/s41575-018-0007-8 (DOI)000433166800010 ()29686404 (PubMedID)2-s2.0-85045834478 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20180613

Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2019-08-20Bibliographically approved
Nielsen, J., Archer, J., Essack, M., Bajic, V. B., Gojobori, T. & Mijakovic, I. (2017). Building a bio-based industry in the Middle East through harnessing the potential of the Red Sea biodiversity. Applied Microbiology and Biotechnology, 101(12), 4837-4851
Open this publication in new window or tab >>Building a bio-based industry in the Middle East through harnessing the potential of the Red Sea biodiversity
Show others...
2017 (English)In: Applied Microbiology and Biotechnology, ISSN 0175-7598, E-ISSN 1432-0614, Vol. 101, no 12, p. 4837-4851Article, review/survey (Refereed) Published
Abstract [en]

The incentive for developing microbial cell factories for production of fuels and chemicals comes from the ability of microbes to deliver these valuable compounds at a reduced cost and with a smaller environmental impact compared to the analogous chemical synthesis. Another crucial advantage of microbes is their great biological diversity, which offers a much larger "catalog" of molecules than the one obtainable by chemical synthesis. Adaptation to different environments is one of the important drives behind microbial diversity. We argue that the Red Sea, which is a rather unique marine niche, represents a remarkable source of biodiversity that can be geared towards economical and sustainable bioproduction processes in the local area and can be competitive in the international bio-based economy. Recent bioprospecting studies, conducted by the King Abdullah University of Science and Technology, have established important leads on the Red Sea biological potential, with newly isolated strains of Bacilli and Cyanobacteria. We argue that these two groups of local organisms are currently most promising in terms of developing cell factories, due to their ability to operate in saline conditions, thus reducing the cost of desalination and sterilization. The ability of Cyanobacteria to perform photosynthesis can be fully exploited in this particular environment with one of the highest levels of irradiation on the planet. We highlight the importance of new experimental and in silico methodologies needed to overcome the hurdles of developing efficient cell factories from the Red Sea isolates.

Place, publisher, year, edition, pages
Springer, 2017
Keywords
Metabolic engineering, Synthetic biology, Industrial biotechnology, Cell factories, Metagenomics
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-210483 (URN)10.1007/s00253-017-8310-9 (DOI)000402712300001 ()28528426 (PubMedID)2-s2.0-85019598546 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceNovo NordiskKnut and Alice Wallenberg FoundationSwedish Research Council
Note

QC 20170705

Available from: 2017-07-05 Created: 2017-07-05 Last updated: 2017-07-05Bibliographically approved
Huang, M., Bao, J., Hallström, B. M., Petranovic, D. & Nielsen, J. (2017). Efficient protein production by yeast requires global tuning of metabolism. Nature Communications, 8(1), Article ID 1131.
Open this publication in new window or tab >>Efficient protein production by yeast requires global tuning of metabolism
Show others...
2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, no 1, article id 1131Article in journal (Refereed) Published
Abstract [en]

The biotech industry relies on cell factories for production of pharmaceutical proteins, of which several are among the top-selling medicines. There is, therefore, considerable interest in improving the efficiency of protein production by cell factories. Protein secretion involves numerous intracellular processes with many underlying mechanisms still remaining unclear. Here, we use RNA-seq to study the genome-wide transcriptional response to protein secretion in mutant yeast strains. We find that many cellular processes have to be attuned to support efficient protein secretion. In particular, altered energy metabolism resulting in reduced respiration and increased fermentation, as well as balancing of amino-acid biosynthesis and reduced thiamine biosynthesis seem to be particularly important. We confirm our findings by inverse engineering and physiological characterization and show that by tuning metabolism cells are able to efficiently secrete recombinant proteins. Our findings provide increased understanding of which cellular regulations and pathways are associated with efficient protein secretion.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
Keywords
amylase, carbohydrate, protein, thiamine, biological production, biotechnology, efficiency measurement, genetic engineering, metabolism, yeast, AAC3 gene, amino acid synthesis, amylase release, ANB1 gene, Article, bacterium culture, carbohydrate metabolism, CYC7 gene, DAN1 gene, endoplasmic reticulum stress, energy metabolism, fermentation, fungal gene, FUR1 gene, genome-wide association study, MSS11 gene, nonhuman, PHO12 gene, PHO84 gene, PHO89 gene, protein metabolism, protein secretion, reporter gene, RNA sequence, SNF2 gene, SPL2 gene, SUT1 gene, SWI4 gene, TEC1 gene, TIR3 gene
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-227126 (URN)10.1038/s41467-017-00999-2 (DOI)000413658300001 ()2-s2.0-85032290095 (Scopus ID)
Note

QC 20180508

Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2019-10-28Bibliographically approved
Zhu, Z., Zhou, Y. J., Kang, M.-K. -., Krivoruchko, A., Buijs, N. A. & Nielsen, J. (2017). Enabling the synthesis of medium chain alkanes and 1-alkenes in yeast. Metabolic engineering, 44, 81-88
Open this publication in new window or tab >>Enabling the synthesis of medium chain alkanes and 1-alkenes in yeast
Show others...
2017 (English)In: Metabolic engineering, ISSN 1096-7176, E-ISSN 1096-7184, Vol. 44, p. 81-88Article in journal (Refereed) Published
Abstract [en]

Microbial synthesis of medium chain aliphatic hydrocarbons, attractive drop-in molecules to gasoline and jet fuels, is a promising way to reduce our reliance on petroleum-based fuels. In this study, we enabled the synthesis of straight chain hydrocarbons (C7–C13) by yeast Saccharomyces cerevisiae through engineering fatty acid synthases to control the chain length of fatty acids and introducing heterologous pathways for alkane or 1-alkene synthesis. We carried out enzyme engineering/screening of the fatty aldehyde deformylating oxygenase (ADO), and compartmentalization of the alkane biosynthesis pathway into peroxisomes to improve alkane production. The two-step synthesis of alkanes was found to be inefficient due to the formation of alcohols derived from aldehyde intermediates. Alternatively, the drain of aldehyde intermediates could be circumvented by introducing a one-step decarboxylation of fatty acids to 1-alkenes, which could be synthesized at a level of 3 mg/L, 25-fold higher than that of alkanes produced via aldehydes.

Place, publisher, year, edition, pages
Academic Press Inc., 2017
Keywords
1-Alkenes, Alkanes, Medium-chain fatty acids, Saccharomyces cerevisiae, Aldehydes, Biochemistry, Carboxylation, Chains, Cytology, Hydrocarbons, Paraffins, Synthesis (chemical), Yeast, Aliphatic hydrocarbons, Biosynthesis pathways, Enzyme engineering, Microbial synthesis, Two-step synthesis, Yeast Saccharomyces cerevisiae, Fatty acids, 1 alkene, alcohol derivative, aldehyde, aldehyde deformylating oxygenase, aliphatic hydrocarbon, alkane, alkene, fatty acid, fatty acid synthase, medium chain fatty acid, oxygenase, unclassified drug, Article, biosynthesis, controlled study, decarboxylation, nonhuman, peroxisome, priority journal, protein expression
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-227064 (URN)10.1016/j.ymben.2017.09.007 (DOI)000416513600009 ()2-s2.0-85030102515 (Scopus ID)
Note

QC 20180517

Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2019-10-18Bibliographically approved
Sweetlove, L. J., Nielsen, J. & Fernie, A. R. (2017). Engineering central metabolism - a grand challenge for plant biologists. The Plant Journal, 90(4), 749-763
Open this publication in new window or tab >>Engineering central metabolism - a grand challenge for plant biologists
2017 (English)In: The Plant Journal, ISSN 0960-7412, E-ISSN 1365-313X, Vol. 90, no 4, p. 749-763Article in journal (Refereed) Published
Abstract [en]

The goal of increasing crop productivity and nutrient-use efficiency is being addressed by a number of ambitious research projects seeking to re-engineer photosynthetic biochemistry. Many of these projects will require the engineering of substantial changes in fluxes of central metabolism. However, as has been amply demonstrated in simpler systems such as microbes, central metabolism is extremely difficult to rationally engineer. This is because of multiple layers of regulation that operate to maintain metabolic steady state and because of the highly connected nature of central metabolism. In this review we discuss new approaches for metabolic engineering that have the potential to address these problems and dramatically improve the success with which we can rationally engineer central metabolism in plants. In particular, we advocate the adoption of an iterative 'design-build-test-learn' cycle using fast-to-transform model plants as test beds. This approach can be realised by coupling new molecular tools to incorporate multiple transgenes in nuclear and plastid genomes with computational modelling to design the engineering strategy and to understand the metabolic phenotype of the engineered organism. We also envisage that mutagenesis could be used to fine-tune the balance between the endogenous metabolic network and the introduced enzymes. Finally, we emphasise the importance of considering the plant as a whole system and not isolated organs: the greatest increase in crop productivity will be achieved if both source and sink metabolism are engineered.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2017
Keywords
metabolic engineering, central metabolism, multi-transgene, computational modelling, source and sink
National Category
Plant Biotechnology
Identifiers
urn:nbn:se:kth:diva-207903 (URN)10.1111/tpj.13484 (DOI)000400641100010 ()28004455 (PubMedID)2-s2.0-85015188264 (Scopus ID)
Note

QC 20170530

Available from: 2017-05-30 Created: 2017-05-30 Last updated: 2017-09-12Bibliographically approved
Fletcher, E., Feizi, A., Bisschops, M. M., Hallström, B. M., Khoomrung, S., Siewers, V. & Nielsen, J. (2017). Evolutionary engineering reveals divergent paths when yeast is adapted to different acidic environments. Metabolic engineering, 39, 19-28
Open this publication in new window or tab >>Evolutionary engineering reveals divergent paths when yeast is adapted to different acidic environments
Show others...
2017 (English)In: Metabolic engineering, ISSN 1096-7176, E-ISSN 1096-7184, Vol. 39, p. 19-28Article in journal (Refereed) Published
Abstract [en]

Tolerance of yeast to acid stress is important for many industrial processes including organic acid production. Therefore, elucidating the molecular basis of long term adaptation to acidic environments will be beneficial for engineering production strains to thrive under such harsh conditions. Previous studies using gene expression analysis have suggested that both organic and inorganic acids display similar responses during short term exposure to acidic conditions. However, biological mechanisms that will lead to long term adaptation of yeast to acidic conditions remains unknown and whether these mechanisms will be similar for tolerance to both organic and inorganic acids is yet to be explored. We therefore evolved Saccharomyces cerevisiae to acquire tolerance to HCl (inorganic acid) and to 0.3 M L-lactic acid (organic acid) at pH 2.8 and then isolated several low pH tolerant strains. Whole genome sequencing and RNA-seq analysis of the evolved strains revealed different sets of genome alterations suggesting a divergence in adaptation to these two acids. An altered sterol composition and impaired iron uptake contributed to HCl tolerance whereas the formation of a multicellular morphology and rapid lactate degradation was crucial for tolerance to high concentrations of lactic acid. Our findings highlight the contribution of both the selection pressure and nature of the acid as a driver for directing the evolutionary path towards tolerance to low pH. The choice of carbon source was also an important factor in the evolutionary process since cells evolved on two different carbon sources (raffinose and glucose) generated a different set of mutations in response to the presence of lactic acid. Therefore, different strategies are required for a rational design of low pH tolerant strains depending on the acid of interest.

Place, publisher, year, edition, pages
Academic Press, 2017
Keywords
Adaptive laboratory evolution, Lactic acid, Low pH, Yeast, Biology, Gene expression, Genes, Inorganic acids, Organic acids, Plants (botany), Biological mechanisms, Different carbon sources, Evolutionary engineering, Evolutionary process, Gene expression analysis, Organic acid productions, Whole genome sequencing
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-202835 (URN)10.1016/j.ymben.2016.10.010 (DOI)000392565200003 ()2-s2.0-85008240309 (Scopus ID)
Funder
Novo NordiskKnut and Alice Wallenberg Foundation
Note

QC 20170320

Available from: 2017-03-20 Created: 2017-03-20 Last updated: 2017-11-29Bibliographically approved
Kang, M.-K., Zhou, Y. J., Buijs, N. A. & Nielsen, J. (2017). Functional screening of aldehyde decarbonylases for long-chain alkane production by Saccharomyces cerevisiae. Microbial Cell Factories, 16, Article ID 74.
Open this publication in new window or tab >>Functional screening of aldehyde decarbonylases for long-chain alkane production by Saccharomyces cerevisiae
2017 (English)In: Microbial Cell Factories, ISSN 1475-2859, E-ISSN 1475-2859, Vol. 16, article id 74Article in journal (Refereed) Published
Abstract [en]

Background: Low catalytic activities of pathway enzymes are often a limitation when using microbial based chemical production. Recent studies indicated that the enzyme activity of aldehyde decarbonylase (AD) is a critical bottleneck for alkane biosynthesis in Saccharomyces cerevisiae. We therefore performed functional screening to identify efficient ADs that can improve alkane production by S. cerevisiae. Results: A comparative study of ADs originated from a plant, insects, and cyanobacteria were conducted in S. cerevisiae. As a result, expression of aldehyde deformylating oxygenases (ADOs), which are cyanobacterial ADs, from Synechococcus elongatus and Crocosphaera watsonii converted fatty aldehydes to corresponding Cn-1 alkanes and alkenes. The CwADO showed the highest alkane titer (0.13 mg/L/OD600) and the lowest fatty alcohol production (0.55 mg/L/OD600). However, no measurable alkanes and alkenes were detected in other AD expressed yeast strains. Dynamic expression of SeADO and CwADO under GAL promoters increased alkane production to 0.20 mg/L/OD600 and no fatty alcohols, with even number chain lengths from C8 to C14, were detected in the cells. Conclusions: We demonstrated in vivo enzyme activities of ADs by displaying profiles of alkanes and fatty alcohols in S. cerevisiae. Among the AD enzymes evaluated, cyanobacteria ADOs were found to be suitable for alkane biosynthesis in S. cerevisiae. This work will be helpful to decide an AD candidate for alkane biosynthesis in S. cerevisiae and it will provide useful information for further investigation of AD enzymes with improved activities.

Place, publisher, year, edition, pages
BioMed Central, 2017
Keywords
Metabolic engineering, Saccharomyces cerevisiae, Alkane biosynthesis, Aldehyde decarbonylase, Biofuels
National Category
Biocatalysis and Enzyme Technology
Identifiers
urn:nbn:se:kth:diva-207888 (URN)10.1186/s12934-017-0683-z (DOI)000400327100001 ()28464872 (PubMedID)2-s2.0-85019099241 (Scopus ID)
Note

QC 20170530

Available from: 2017-05-30 Created: 2017-05-30 Last updated: 2017-11-29Bibliographically approved
Bosley, J., Borén, C., Lee, S., Grotli, M., Nielsen, J., Uhlén, M., . . . Mardinoglu, A. (2017). Improving the economics of NASH/NAFLD treatment through the use of systems biology. Drug Discovery Today, 22(10), 1532-1538
Open this publication in new window or tab >>Improving the economics of NASH/NAFLD treatment through the use of systems biology
Show others...
2017 (English)In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 22, no 10, p. 1532-1538Article, review/survey (Refereed) Published
Abstract [en]

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD). We surveyed NASH therapies currently in development, and found a significant variety of targets and approaches. Evaluation and clinical testing of these targets is an expensive and time-consuming process. Systems biology approaches could enable the quantitative evaluation of the likely efficacy and safety of different targets. This motivated our review of recent systems biology studies that focus on the identification of targets and development of effective treatments for NASH. We discuss the potential broader use of genome-scale metabolic models and integrated networks in the validation of drug targets, which could facilitate more productive and efficient drug development decisions for the treatment of NASH.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2017
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:kth:diva-217446 (URN)10.1016/j.drudis.2017.07.005 (DOI)000413799500008 ()28736156 (PubMedID)2-s2.0-85026322326 (Scopus ID)
Note

QC 20171117

Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2018-01-13Bibliographically approved
Organisations

Search in DiVA

Show all publications