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1. IL-33 and MRGPRX2-Triggered Activation of Human Skin Mast Cells—Elimination of Receptor Expression on Chronic Exposure, but Reinforced Degranulation on Acute Priming

Author

Wang, Zhao, Guhl, Sven, Franke, Kristin, Artuc, Metin, Zuberbier, Torsten, and Babina, Magda

Subjects
Receptors, Neuropeptide, skin, MAP Kinase Signaling System, Nerve Tissue Proteins, mast cells, p38, Cell Degranulation, Article, Receptors, G-Protein-Coupled, pseudo-allergy, Humans, lcsh:QH301-705.5, Cells, Cultured, degranulation, fungi, JNK Mitogen-Activated Protein Kinases, neurogenic mast cell activation, neuropeptides, food and beverages, Interleukin-33, lcsh:Biology (General), IL-33, MRGPRX2, JNK, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
Abstract

Clinically relevant exocytosis of mast cell (MC) mediators can be triggered by high-affinity IgE receptor (Fc&epsilon, RI)-aggregation (allergic route) or by the so-called pseudo-allergic pathway elicited via MAS-related G protein-coupled receptor-X2 (MRGPRX2). The latter is activated by drugs and endogenous neuropeptides. We recently reported that Fc&epsilon, RI-triggered degranulation is attenuated when human skin mast cells are chronically exposed to IL-33. Here, we were interested in the regulation of the MRGPRX2-route. Chronic exposure of skin MCs to IL-33 basically eliminated the pseudo-allergic/neurogenic route as a result of massive MRGPRX2 reduction. This downregulation seemed to partially require c-Jun N-terminal Kinase (JNK), but not p38, the two kinases activated by IL-33 in skin MCs. Surprisingly, however, JNK had a positive effect on MRGPRX2 expression in the absence of IL-33. This was evidenced by Accell&reg, mediated JNK knockdown and JNK inhibition. In stark contrast to the dampening effect upon prolonged exposure, IL-33 was able to prime for increased degranulation by MRGPRX2 ligands when administered directly before stimulation. This supportive effect depended on p38, but not on JNK activity. Our data reinforce the concept that exposure length dictates whether IL-33 will enhance or attenuate secretion. IL-33 is, thus, the first factor to acutely enhance MRGPRX2-triggered degranulation. Finally, we reveal that p38, rarely associated with MC degranulation, can positively affect exocytosis in a context-dependent manner.

Published
2019
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2. An integrated expression atlas of miRNAs and their promoters in human and mouse

Author

de Rie, Yoko, Abugessaisa, Yoko, Alam, Tanvir, Arner, Yoko, Arner, Peter, Ha, Haitham, Aström, Gaby, Babina, Magda, Bertin, Yoko, Burroughs, Yoko, Carlisle, Ailsa, Daub, Yoko, Detmar, Michael, Deviatiiarov, Yoko, Fort, Yoko, Gebhard, Claudia, Goldowitz, Daniel, Guhl, Sven, Ha, Thomas, Harshbarger, Yoko, Hasegawa, Yoko, Hashimoto, Yoko, Herlyn, Meenhard, Heutink, Peter, Hitchens, Kelly, Hon, Yoko, Huang, Edward, Ishizu, Yoko, Kai, Chieko, Kasukawa, Yoko, Klinken, Peter, Lassmann, Yoko, Lecellier, Charles-Henri, Lee, Weonju, Lizio, Yoko, Makeev, Vsevolod, Mathelier, Anthony, Medvedeva, Yulia, Mejhert, Niklas, Mungall, Christopher, Noma, Yoko, Ohshima, Mitsuhiro, Okada-Hatakeyama, Yoko, Persson, Helena, Rizzu, Patrizia, Roudnicky, Filip, Sætrom, Pål, Sato, Hiroki, Severin, Yoko, Shin, Yoko, Swoboda, Rolf, Tarui, Yoko, Toyoda, Hiroo, Vitting-Seerup, Kristoffer, Winteringham, Louise, Yamaguchi, Yoko, Yasuzawa, Kayoko, Yoneda, Misako, Yumoto, Noriko, Zabierowski, Susan, Zhang, Peter, Wells, Christine, Summers, Kim, Kawaji, Hideya, Sandelin, Albin, Rehli, Michael, Hayashizaki, Yoshihide, Carninci, Piero, Forrest, Alistair, de Hoon, Michiel, de Rie, Derek, Abugessaisa, Imad, Arner, Erik, Ashoor, Haitham, Bertin, Nicolas, Burroughs, A Maxwell, Daub, Carsten, Deviatiiarov, Ruslan, Fort, Alexandre, Ha, Jayson, Ha, Akira, Ha, Kosuke, Hon, Chung Chau, Ishizu, Yuri, Kasukawa, Takeya, Lassmann, Timo, Lizio, Marina, Noma, Shohei, Ha, Mariko, Severin, Jessica, Shin, Jay, Tarui, Hiroshi, Ha, Yoshihide, Computat Biosci Res Ctr, Comp Elect & Math Sci & Engn Div, King Abdullah University of Science and Technology (KAUST), Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Dept Dermatol & Allergy, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Clinical Genetics, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institute of Genetics and Selection of Industrial Microorganisms, GosNIIGenetika, Centre for Molecular Medicine Norway (NCMM), Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Department of Oncology, Lund University [Lund]-Clinical Sciences, RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), University of Copenhagen = Københavns Universitet (KU), Cold Spring Harbor Laboratory, RIKEN Center for Life Science Technologies (RIKEN CLST), Ctr Life Sci Technol, Div Gen Technol, Tsurumi Ku, Karolinska Institutet [Stockholm], Department of Genetic Medicine and Development [Geneva], Université de Genève (UNIGE), Riken Omics Science Center, and Riken Yokohama Institute

Subjects
0301 basic medicine, FANTOM Consortium, Cells, Biomedical Engineering, Bioengineering, Biology, Applied Microbiology and Biotechnology, Genome, Article, Promoter Regions, 03 medical and health sciences, Mice, Genetic, Transcription (biology), metabolism [MicroRNAs], [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, Gene expression, Transcriptional regulation, Gene silencing, Animals, Humans, genetics [MicroRNAs], Promoter Regions, Genetic, Cells, Cultured, Gene Library, Genetics, Cultured, Gene Expression Profiling, RNA, High-Throughput Nucleotide Sequencing, Molecular Sequence Annotation, Gene expression profiling, MicroRNAs, 030104 developmental biology, Good Health and Well Being, genetics [Promoter Regions, Genetic], ddc:660, Molecular Medicine, Generic health relevance, Biotechnology, methods [Gene Expression Profiling]
Abstract

International audience; MicroRNAs (miRNAs) are short non-coding RNAs with key roles in cellular regulation. As part of the fifth edition of the Functional Annotation of Mammalian Genome (FANTOM5) project, we created an integrated expression atlas of miRNAs and their promoters by deep-sequencing 492 short RNA (sRNA) libraries, with matching Cap Analysis Gene Expression (CAGE) data, from 396 human and 47 mouse RNA samples. Promoters were identified for 1,357 human and 804 mouse miRNAs and showed strong sequence conservation between species. We also found that primary and mature miRNA expression levels were correlated, allowing us to use the primary miRNA measurements as a proxy for mature miRNA levels in a total of 1,829 human and 1,029 mouse CAGE libraries. We thus provide a broad atlas of miRNA expression and promoters in primary mammalian cells, establishing a foundation for detailed analysis of miRNA expression patterns and transcriptional control regions.

Published
2017

3. Data Descriptor : FANTOM5 CAGE profiles of human and mouse samples

Author

Noguchi, Shuhei, Arakawa, Takahiro, Fukuda, Shiro, Furuno, Masaaki, Hasegawa, Akira, Hori, Fumi, Ishikawa-Kato, Sachi, Kaida, Kaoru, Kaiho, Ai, Kanamori-Katayama, Mutsumi, Kawashima, Tsugumi, Kojima, Miki, Kubosaki, Atsutaka, Manabe, Ri-ichiroh, Murata, Mitsuyoshi, Nagao-Sato, Sayaka, Nakazato, Kenichi, Ninomiya, Noriko, Nishiyori-Sueki, Hiromi, Noma, Shohei, Saijyo, Eri, Saka, Akiko, Sakai, Mizuho, Simon, Christophe, Suzuki, Naoko, Tagami, Michihira, Watanabe, Shoko, Yoshida, Shigehiro, Arner, Peter, Axton, Richard A., Babina, Magda, Baillie, J. Kenneth, Barnett, Timothy C., Beckhouse, Anthony G., Blumenthal, Antje, Bodega, Beatrice, Bonetti, Alessandro, Briggs, James, Brombacher, Frank, Carlisle, Ailsa J., Clevers, Hans C., Davis, Carrie A., Detmar, Michael, Dohi, Taeko, Edge, Albert S. B., Edinger, Matthias, Ehrlund, Anna, Ekwall, Karl, Endoh, Mitsuhiro, Enomoto, Hideki, Eslami, Afsaneh, Fagiolini, Michela, Fairbairn, Lynsey, Farach-Carson, Mary C., Faulkner, Geoffrey J., Ferrai, Carmelo, Fisher, Malcolm E., Forrester, Lesley M., Fujita, Rie, Furusawa, Jun-ichi, Geijtenbeek, Teunis B., Gingeras, Thomas, Goldowitz, Daniel, Guhl, Sven, Guler, Reto, Gustincich, Stefano, Ha, Thomas J., Hamaguchi, Masahide, Hara, Mitsuko, Hasegawa, Yuki, Herlyn, Meenhard, Heutink, Peter, Hitchens, Kelly J., Hume, David A., Ikawa, Tomokatsu, Ishizu, Yuri, Kai, Chieko, Kawamoto, Hiroshi, Kawamura, Yuki I., Kempfle, Judith S., Kenna, Tony J., Kere, Juha, Khachigian, Levon M., Kitamura, Toshio, Klein, Sarah, Klinken, S. Peter, Knox, Alan J., Kojima, Soichi, Koseki, Haruhiko, Koyasu, Shigeo, Lee, Weonju, Lennartsson, Andreas, Mackay-sim, Alan, Mejhert, Niklas, Mizuno, Yosuke, Morikawa, Hiromasa, Morimoto, Mitsuru, Moro, Kazuyo, Morris, Kelly J., Motohashi, Hozumi, Mummery, Christine L., Nakachi, Yutaka, Nakahara, Fumio, Nakamura, Toshiyuki, Nakamura, Yukio, Nozaki, Tadasuke, Ogishima, Soichi, Ohkura, Naganari, Ohno, Hiroshi, Ohshima, Mitsuhiro, Okada-Hatakeyama, Mariko, Okazaki, Yasushi, Orlando, Valerio, Ovchinnikov, Dmitry A., Passier, Robert, Patrikakis, Margaret, Pombo, Ana, Pradhan-Bhatt, Swati, Qin, Xian-Yang, Rehli, Michael, Rizzu, Patrizia, Roy, Sugata, Sajantila, Antti, Sakaguchi, Shimon, Sato, Hiroki, Satoh, Hironori, Savvi, Suzana, Saxena, Alka, Schmidl, Christian, Schneider, Claudio, Schulze-Tanzil, Gundula G., Schwegmann, Anita, Sheng, Guojun, Shin, Jay W., Sugiyama, Daisuke, Sugiyama, Takaaki, Summers, Kim M., Takahashi, Naoko, Takai, Jun, Tanaka, Hiroshi, Tatsukawa, Hideki, Tomoiu, Andru, Toyoda, Hiroo, van de Wetering, Marc, van den Berg, Linda M., Verardo, Roberto, Vijayan, Dipti, Wells, Christine A., Winteringham, Louise N., Wolvetang, Ernst, Yamaguchi, Yoko, Yamamoto, Masayuki, Yanagi-Mizuochi, Chiyo, Yoneda, Misako, Yonekura, Yohei, Zhang, Peter G., Zucchelli, Silvia, Abugessaisa, Imad, Arner, Erik, Harshbarger, Jayson, Kondo, Atsushi, Lassmann, Timo, Lizio, Marina, Sahin, Serkan, Sengstag, Thierry, Severin, Jessica, Shimoji, Hisashi, Suzuki, Masanori, Suzuki, Harukazu, Kawai, Jun, Kondo, Naoto, Itoh, Masayoshi, Daub, Carsten O., Kasukawa, Takeya, Kawaji, Hideya, Carninci, Piero, Forrest, Alistair R. R., Hayashizaki, Yoshihide, Medicum, University of Helsinki, Forensic Medicine, Department of Forensic Medicine, and PaleOmics Laboratory

Subjects
ENHANCERS, MAMMALIAN-CELLS, UCSC GENOME BROWSER, VISUALIZATION, UPDATE, GROWTH, IN-VITRO, TRANSCRIPTION, 3111 Biomedicine, ATLAS, GENE-EXPRESSION
Abstract

In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.

Published
2017

4. The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome

Author

Hurst, Laurence D., Ghanbarian, Avazeh T., Forrest, Alistair R R, Huminiecki, Lukasz, Rehli, Michael, Kenneth Baillie, J., de Hoon, Michiel J L, Haberle, Vanja, Lassmann, Timo, Kulakovskiy, Ivan V., Lizio, Marina, Itoh, Masayoshi, Andersson, Robin, Mungall, Christopher J., Meehan, Terrence F., Schmeier, Sebastian, Bertin, Nicolas, Jørgensen, Mette, Dimont, Emmanuel, Arner, Erik, Schmidl, Christian, Schaefer, Ulf, Medvedeva, Yulia A., Plessy, Charles, Vitezic, Morana, Severin, Jessica, Semple, Colin A., Ishizu, Yuri, Young, Robert S., Francescatto, Margherita, Alam, Intikhab, Albanese, Davide, Altschuler, Gabriel M., Arakawa, Takahiro, Archer, John A C, Arner, Peter, Babina, Magda, Baker, Sarah, Balwierz, Piotr J., Beckhouse, Anthony G., Pradhan, Swati Bhatt, Blake, Judith A., Blumenthal, Antje, Bodega, Beatrice, Bonetti, Alessandro, Briggs, James, Brombacher, Frank, Maxwell Burroughs, A., Califano, Andrea, Cannistraci, Carlo V., Carbajo, Daniel, Chen, Yun, Chierici, Marco, Ciani, Yari, Clevers, Hans C., Dalla, Emiliano, Davis, Carrie A., Detmar, Michael, Diehl, Alexander D., Dohi, Taeko, Drabløs, Finn, Edge, Albert S B, Edinger, Matthias, Ekwall, Karl, Endoh, Mitsuhiro, Enomoto, Hideki, Fagiolini, Michela, Fairbairn, Lynsey, Fang, Hai, Farach-Carson, Mary C., Faulkner, Geoffrey J., Favorov, Alexander V., Fisher, Malcolm E., Frith, Martin C., Fujita, Rie, Fukuda, Shiro, Furlanello, Cesare, Furuno, Masaaki, Furusawa, Jun ichi, Geijtenbeek, Teunis B., Gibson, Andrew, Gingeras, Thomas, Goldowitz, Daniel, Gough, Julian, Guhl, Sven, Guler, Reto, Gustincich, Stefano, Ha, Thomas J., Hamaguchi, Masahide, Hara, Mitsuko, Harbers, Matthias, Harshbarger, Jayson, Hasegawa, Akira, Hasegawa, Yuki, Hashimoto, Takehiro, Herlyn, Meenhard, Hitchens, Kelly J., Ho Sui, Shannan J., Hofmann, Oliver M., Hoof, Ilka, Hori, Fumi, Iida, Kei, Ikawa, Tomokatsu, Jankovic, Boris R., Jia, Hui, Joshi, Anagha, Jurman, Giuseppe, Kaczkowski, Bogumil, Kai, Chieko, Kaida, Kaoru, Kaiho, Ai, Kajiyama, Kazuhiro, Kanamori, Mutsumi Katayama, Kasianov, Artem S., Kasukawa, Takeya, Katayama, Shintaro, Kato, Sachi, Kawaguchi, Shuji, Kawamoto, Hiroshi, Kawamura, Yuki I., Kawashima, Tsugumi, Kempfle, Judith S., Kenna, Tony J., Kere, Juha, Khachigian, Levon M., Kitamura, Toshio, Peter Klinken, S., Knox, Alan J., Kojima, Miki, Kojima, Soichi, Kondo, Naoto, Koseki, Haruhiko, Koyasu, Shigeo, Krampitz, Sarah, Kubosaki, Atsutaka, Kwon, Andrew T., Laros, Jeroen F J, Lee, Weonju, Lennartsson, Andreas, Li, Kang, Lilje, Berit, Lipovich, Leonard, Mackay, Alan sim, Manabe, Riichiroh, Mar, Jessica C., Marchand, Benoit, Mathelier, Anthony, Mejhert, Niklas, Meynert, Alison, Mizuno, Yosuke, de Lima Morais, David A., Morikawa, Hiromasa, Morimoto, Mitsuru, Moro, Kazuyo, Motakis, Efthymios, Motohashi, Hozumi, Mummery, Christine L., Murata, Mitsuyoshi, Nagao, Sayaka Sato, Nakachi, Yutaka, Nakahara, Fumio, Nakamura, Toshiyuki, Nakamura, Yukio, Nakazato, Kenichi, van Nimwegen, Erik, Ninomiya, Noriko, Nishiyori, Hiromi, Noma, Shohei, Nozaki, Tadasuke, Ogishima, Soichi, Ohkura, Naganari, Ohmiya, Hiroko, Ohno, Hiroshi, Ohshima, Mitsuhiro, Okada, Mariko Hatakeyama, Okazaki, Yasushi, Orlando, Valerio, Ovchinnikov, Dmitry A., Pain, Arnab, Passier, Robert, Patrikakis, Margaret, Persson, Helena, Piazza, Silvano, Prendergast, James G D, Rackham, Owen J L, Ramilowski, Jordan A., Rashid, Mamoon, Ravasi, Timothy, Rizzu, Patrizia, Roncador, Marco, Roy, Sugata, Rye, Morten B., Saijyo, Eri, Sajantila, Antti, Saka, Akiko, Sakaguchi, Shimon, Sakai, Mizuho, Sato, Hiroki, Satoh, Hironori, Savvi, Suzana, Saxena, Alka, Schneider, Claudio, Schultes, Erik A., Schulze-Tanzil, Gundula G., Schwegmann, Anita, Sengstag, Thierry, Sheng, Guojun, Shimoji, Hisashi, Shimoni, Yishai, Shin, Jay W., Simon, Christophe, Sugiyama, Daisuke, Sugiyama, Takaaki, Suzuki, Masanori, Suzuki, Naoko, Swoboda, Rolf K., 't Hoen, Peter A C, Tagami, Michihira, Takahashi, Naoko, Takai, Jun, Tanaka, Hiroshi, Tatsukawa, Hideki, Tatum, Zuotian, Thompson, Mark, Toyoda, Hiroo, Toyoda, Tetsuro, Valen, Eivind, van de Wetering, Marc, van den Berg, Linda M., Verardo, Roberto, Vijayan, Dipti, Vorontsov, Ilya E., Wasserman, Wyeth W., Watanabe, Shoko, Wells, Christine A., Winteringham, Louise N., Wolvetang, Ernst, Wood, Emily J., Yamaguchi, Yoko, Yamamoto, Masayuki, Yoneda, Misako, Yonekura, Yohei, Yoshida, Shigehiro, Zabierowski, Suzan E., Zhang, Peter G., Zhao, Xiaobei, Zucchelli, Silvia, Summers, Kim M., Suzuki, Harukazu, Daub, Carsten O., Kawai, Jun, Heutink, Peter, Hide, Winston, Freeman, Tom C., Lenhard, Boris, Bajic, Vladimir B., Taylor, Martin S., Makeev, Vsevolod J., Sandelin, Albin Gustav, Hume, David A., Carninci, Piero, Hayashizaki, Yoshihide, Hubrecht Institute for Developmental Biology and Stem Cell Research, Barton, Nick H, Amsterdam institute for Infection and Immunity, Infectious diseases, and Experimental Immunology

Subjects
Male, Medical and Health Sciences, Essential, Models, Gene expression, Databases, Genetic, Biology (General), Non-U.S. Gov't, X-linked recessive inheritance, X chromosome, Cells, Cultured, Regulation of gene expression, Genetics, Sex Characteristics, Dosage compensation, Tumor, Cultured, Genes, Essential, Genome, Agricultural and Biological Sciences(all), General Neuroscience, Research Support, Non-U.S. Gov't, Biological Sciences, Organ Specificity, Female, General Agricultural and Biological Sciences, Research Article, Human, X Chromosome, Retroelements, QH301-705.5, Neuroscience(all), 1.1 Normal biological development and functioning, Cells, Down-Regulation, Biology, Research Support, General Biochemistry, Genetics and Molecular Biology, Chromosomes, Cell Line, Databases, Genetic, Species Specificity, Underpinning research, Immunology and Microbiology(all), Cell Line, Tumor, Journal Article, Animals, Humans, Comparative Study, Gene, Chromosomes, Human, X, Autosome, General Immunology and Microbiology, Agricultural and Veterinary Sciences, Models, Genetic, Biochemistry, Genetics and Molecular Biology(all), Genome, Human, Mammalian, Human Genome, Chromosomes, Mammalian, Genes, Gene Expression Regulation, Human genome, FANTOM consortium, Developmental Biology
Abstract

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X’s gene content, gene expression, and evolution., Laurence Hurst, Lukasz Huminiecki, and the FANTOM5 consortium propose a new explanation for the peculiar expression properties of genes on the human X chromosome, based on the premise that very high expression levels cannot be achieved on a haploid-expressed chromosome., Author Summary Genes located on the human X chromosome are not a random mix of genes: they tend to be expressed in relatively few tissues or are specific for a particular set of tissues, e.g., brain regions. Prior attempts to explain this skewed gene content have hypothesized that the X chromosome might be peculiar because it has to balance mutations that are advantageous to one sex but deleterious to the other, or because it has to shut down during the process of sperm manufacture in males. Here we suggest and test a third possible explanation: that genes on the X chromosome are limited in their transcription levels and thus tend to be genes that are lowly or specifically expressed. We consider the suggestion that since these genes can only be expressed from one chromosome, as males only have one X, the ability to express a gene at very high rates is limited owing to potential transcriptional traffic jams. As predicted, we find that human X-located genes have maximal expression rates far below that of genes residing on autosomes. When we look at genes that have moved onto or off the X chromosome during recent evolution, we find the maximal expression is higher when not on the X chromosome. We also find that X-located genes that are relatively highly expressed are not able to increase their expression level further. Our model explains both the enrichment for tissue specificity and the paucity of certain tissues with X-located genes. Genes underrepresented on the X are either expressed in many tissues—such genes tend to have high maximal expression—or are from tissues that require a lot of transcription (e.g., fast secreting tissues like the liver). Just as many of the findings cannot be explained by the two earlier models, neither can the traffic jam model explain all the peculiar features of the genes found on the X chromosome. Indeed, we find evidence of a reproduction-related bias in X-located genes, even after allowing for the traffic jam problem.

Published
2015

5. Mast cell-derived TNF-α and histamine modify IL-6 and IL-8 expression and release from cutaneous tumor cells

Author

Artuc, Metin, Guhl, Sven, Babina, Magda, Unger, Thomas, Steckelings, Ulrike Muscha, and Zuberbier, Torsten

Abstract

The coincidence of skin tumors and elevated mast cell (MC) numbers has been known for many years. However, it has remained controversial whether, in this context, MCs promote or inhibit tumor growth. Addressing this problem, different melanoma and squamous cell carcinoma cell lines were co-cultivated with primary, dermal MC for 24 h and gene or protein expression of cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) estimated. Co-culture with MCs led to an increase in IL-8 gene expression and IL-8 protein release from melanoma cells and IL-6 and IL-8 gene expression and protein release from squamous cell carcinoma cells, respectively. Moreover induction of IL-6 and IL-8 was primarily regulated by MC-derived TNF-α. Our data suggest an interplay between MCs and tumor cells, which results in altered cytokine release and may, thus, have an impact on tumor growth, invasion and neovascularisation.

Published
2011

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