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2. Discovery of Molecular Markers to Discriminate Corneal Endothelial Cells in the Human Body

Author

Masahito, Y., Hiroko, O., Susumu, H., Satoshi, K., Alistair R, R.F., Hideya, K., Michael, R., J Kenneth Baillie, Michiel J, L.D.H., Vanja, H., Timo, L., Ivan, V.K., Marina, L., Masayoshi, I., Robin, A., Christopher, J.M., Terrence, F.M., Sebastian, S., Nicolas, B., Mette, J., Emmanuel, D., Erik, A., Christian, S., Ulf, S., Yulia, A.M., Charles, P., Morana, V., Jessica, S., Colin, A.S., Yuri, I., Margherita, F., Intikhab, A., Davide, A., Gabriel, M.A., John A, C.A., Peter, A., Magda, B., Sarah, B., Piotr, J.B., Anthony, G.B., Swati, P., Judith, A.B., Antje, B., Bodega, B., Alessandro, B., James, B., Frank, B., A Maxwell Burroughs, Andrea, C., Carlo, V.C., Daniel, C., Yun, C., Marco, C., Yari, C., Hans, C.C., Emiliano, D., Carrie, A.D., Michael, D., Alexander, D.D., Taeko, D., Finn, D., Albert S, B.E., Matthias, E., Karl, E., Mitsuhiro, E., Hideki, E., Michela, F., Lynsey, F., Hai, F., Mary, C.F., Geoffrey, J.F., Alexander, V.F., Malcolm, E.F., Martin, C.F., Rie, F., Shiro, F., Cesare, F., Masaaki, F., Jun-ichi, F., Teunis, B.G., Andrew, G., Thomas, G., Daniel, G., Julian, G., Sven, G., Reto, G., Stefano, G., Thomas, J.H., Masahide, H., Mitsuko, H., Matthias, H., Jayson, H., Akira, H., Yuki, H., Takehiro, H., Meenhard, H., Kelly, J.H., Shannan, J.H.S., Oliver, M.H., Ilka, H., Fumi, H., Lukasz, H., Kei, I., Tomokatsu, I., Boris, R.J., Hui, J., Anagha, J., Giuseppe, J., Bogumil, K., Chieko, K., Kaoru, K., Kaiho, A., Kazuhiro, K., Mutsumi, K., Artem, S.K., Takeya, K., Shintaro, K., Sachi, K., Shuji, K., Hiroshi, K., Yuki, I.K., Tsugumi, K., Judith, S.K., Tony, J.K., Juha, K., Levon, M.K., Toshio, K., S Peter Klinken, Alan, J.K., Miki, K., Soichi, K., Naoto, K., Haruhiko, K., Shigeo, K., Sarah, K., Atsutaka, K., Andrew, T.K., Jeroen F, J.L., Weonju, L., Andreas, L., Kang, L., Berit, L., Leonard, L., Alan, M., Ri-ichiroh, M., Jessica, C.M., Benoit, M., Anthony, M., Niklas, M., Alison, M., Yosuke, M., David, A.D.L.M., Hiromasa, M., Mitsuru, M., Kazuyo, M., Efthymios, M., Hozumi, M., Christine, L.M., Mitsuyoshi, M., Sayaka, N., Yutaka, N., Fumio, N., Toshiyuki, N., Yukio, N., Kenichi, N., Erik van Nimwegen, Noriko, N., Hiromi, N., Shohei, N., Tadasuke, N., Soichi, O., Naganari, O., Hiroshi, O., Mitsuhiro, O., Mariko, O., Yasushi, O., Valerio, O., Dmitry, A.O., Arnab, P., Robert, P., Margaret, P., Helena, P., Silvano, P., James G, D.P., Owen J, L.R., Jordan, A.R., Mamoon, R., Timothy, R., Patrizia, R., Marco, R., Sugata, R., Morten, B.R., Eri, S., Antti, S., Akiko, S., Shimon, S., Mizuho, S., Hiroki, S., Hironori, S., Suzana, S., Alka, S., Claudio, S., Erik, A.S., Gundula, G.S., Anita, S., Thierry, S., Guojun, S., Hisashi, S., Yishai, S., Jay, W.S., Christophe, S., Daisuke, S., Takaaki, S., Masanori, S., Rolf, K.S., Peter A, C.'.H., Michihira, T., Naoko, T., Jun, T., Hiroshi, T., Hideki, T., Zuotian, T., Mark, T., Hiroo, T., Tetsuro, T., Eivind, V., Marc van de Wetering, Linda, M.V.D.B., Roberto, V., Dipti, V., Ilya, E.V., Wyeth, W.W., Shoko, W., Christine, A.W., Louise, N.W., Ernst, W., Emily, J.W., Yoko, Y., Masayuki, Y., Misako, Y., Yohei, Y., Shigehiro, Y., Suzan, E.Z., Peter, G.Z., Xiaobei, Z., Silvia, Z., Kim, M.S., Harukazu, S., Carsten, O.D., Jun, K., Peter, H., Winston, H., Tom, C.F., Boris, L., Vladimir, B.B., Martin, S.T., Vsevolod, J.M., Albin, S., David, A.H., Piero, C., Yoshihide Hayashizaki Yoshihide, H., Motokazu, T., Kohji, N., Hubrecht Institute for Developmental Biology and Stem Cell Research, Amsterdam institute for Infection and Immunity, Infectious diseases, and Experimental Immunology

Subjects
Cell type, Corneal endothelium, Pathology, medicine.medical_specialty, medicine.medical_treatment, lcsh:Medicine, Settore BIO/11 - Biologia Molecolare, Nerve Tissue Proteins, Context (language use), Biology, Zona Pellucida Glycoproteins, Receptors, G-Protein-Coupled, Cornea, Corneal Transplantation, medicine, Humans, Regeneration, Endothelial dysfunction, lcsh:Science, Corneal transplantation, Membrane Glycoproteins, Multidisciplinary, Tissue Engineering, Regeneration (biology), lcsh:R, Egg Proteins, Endothelium, Corneal, Endothelial Cells, Membrane Proteins, Correction, Middle Aged, medicine.disease, medicine.anatomical_structure, Receptor, Serotonin, 5-HT1D, Bullous keratopathy, cardiovascular system, lcsh:Q, Carrier Proteins, Biomarkers, Research Article
Abstract

The corneal endothelium is a monolayer of hexagonal corneal endothelial cells (CECs) on the inner surface of the cornea. CECs are critical in maintaining corneal transparency through their barrier and pump functions. CECs in vivo have a limited capacity in proliferation, and loss of a significant number of CECs results in corneal edema called bullous keratopathy which can lead to severe visual loss. Corneal transplantation is the most effective method to treat corneal endothelial dysfunction, where it suffers from donor shortage. Therefore, regeneration of CECs from other cell types attracts increasing interests, and specific markers of CECs are crucial to identify actual CECs. However, the currently used markers are far from satisfactory because of their non-specific expression in other cell types. Here, we explored molecular markers to discriminate CECs from other cell types in the human body by integrating the published RNA-seq data of CECs and the FANTOM5 atlas representing diverse range of cell types based on expression patterns. We identified five genes, CLRN1, MRGPRX3, HTR1D, GRIP1 and ZP4 as novel markers of CECs, and the specificities of these genes were successfully confirmed by independent experiments at both the RNA and protein levels. Notably none of them have been documented in the context of CEC function. These markers could be useful for the purification of actual CECs, and also available for the evaluation of the products derived from other cell types. Our results demonstrate an effective approach to identify molecular markers for CECs and open the door for the regeneration of CECs in vitro.

Published
2015

3. Ceruloplasmin is a novel adipokine which is overexpressed in adipose tissue of obese subjects and in obesity-associated cancer cells

Author

Arner, E., Forrest, A.R.R., Hideya, K., Michael, R., J Kenneth Baillie, Michiel J, L.D.H., Vanja, H., Timo, L., Ivan, V.K., Marina, L., Masayoshi, I., Robin, A., Christopher, J.M., Terrence, F.M., Sebastian, S., Nicolas, B., Mette, J., Emmanuel, D., Erik, A., Christian, S., Ulf, S., Yulia, A.M., Charles, P., Morana, V., Jessica, S., Colin, A.S., Yuri, I., Margherita, F., Intikhab, A., Davide, A., Gabriel, M.A., John A, C.A., Peter, A., Magda, B., Sarah, B., Piotr, J.B., Anthony, G.B., Swati, P., Judith, A.B., Antje, B., Bodega, B., Alessandro, B., James, B., Frank, B., A Maxwell Burroughs, Andrea, C., Carlo, V.C., Daniel, C., Yun, C., Marco, C., Yari, C., Hans, C.C., Emiliano, D., Carrie, A.D., Michael, D., Alexander, D.D., Taeko, D., Albert S, B.E., Matthias, E., Karl, E., Mitsuhiro, E., Hideki, E., Michela, F., Lynsey, F., Hai, F., Mary, C.F., Geoffrey, J.F., Alexander, V.F., Malcolm, E.F., Martin, C.F., Rie, F., Shiro, F., Cesare, F., Masaaki, F., Jun-ichi, F., Teunis, B.G., Andrew, G., Thomas, G., Daniel, G., Julian, G., Sven, G., Reto, G., Stefano, G., Thomas, J.H., Masahide, H., Mitsuko, H., Matthias, H., Jayson, H., Akira, H., Yuki, H., Takehiro, H., Meenhard, H., Kelly, J.H., Shannan, J.H.S., Oliver, M.H., Ilka, H., Fumi, H., Lukasz, H., Kei, I., Tomokatsu, I., Boris, R.J., Hui, J., Anagha, J., Giuseppe, J., Bogumil, K., Chieko, K., Kaoru, K., Kaiho, A., Kazuhiro, K., Mutsumi, K., Artem, S.K., Takeya, K., Shintaro, K., Sachi, K., Shuji, K., Hiroshi, K., Yuki, I.K., Tsugumi, K., Judith, S.K., Tony, J.K., Juha, K., Levon, M.K., Toshio, K., S Peter Klinken, Alan, J.K., Miki, K., Soichi, K., Naoto, K., Haruhiko, K., Shigeo, K., Sarah, K., Atsutaka, K., Andrew, T.K., Jeroen F, J.L., Weonju, L., Andreas, L., Kang, L., Berit, L., Leonard, L., Alan, M., Ri-ichiroh, M., Jessica, C.M., Benoit, M., Anthony, M., Niklas, M., Alison, M., Yosuke, M., David, A.D.L.M., Hiromasa, M., Mitsuru, M., Kazuyo, M., Efthymios, M., Hozumi, M., Christine, L.M., Mitsuyoshi, M., Sayaka, N., Yutaka, N., Fumio, N., Toshiyuki, N., Yukio, N., Kenichi, N., Erik van Nimwegen, Noriko, N., Hiromi, N., Shohei, N., Tadasuke, N., Soichi, O., Naganari, O., Hiroko, O., Hiroshi, O., Mitsuhiro, O., Mariko, O., Yasushi, O., Valerio, O., Dmitry, A.O., Arnab, P., Robert, P., Margaret, P., Helena, P., Silvano, P., James G, D.P., Owen J, L.R., Jordan, A.R., Mamoon, R., Timothy, R., Patrizia, R., Marco, R., Sugata, R., Morten, B.R., Eri, S., Antti, S., Akiko, S., Shimon, S., Mizuho, S., Hiroki, S., Hironori, S., Suzana, S., Alka, S., Claudio, S., Erik, A.S., Gundula, G.S., Anita, S., Thierry, S., Guojun, S., Hisashi, S., Yishai, S., Jay, W.S., Christophe, S., Daisuke, S., Takaaki, S., Masanori, S., Rolf, K.S., Peter A, C.'.H., Michihira, T., Naoko, T., Jun, T., Hiroshi, T., Hideki, T., Zuotian, T., Mark, T., Hiroo, T., Tetsuro, T., Eivind, V., Marc van de Wetering, Linda, M.V.D.B., Roberto, V., Dipti, V., Ilya, E.V., Wyeth, W.W., Shoko, W., Christine, A.W., Louise, N.W., Ernst, W., Emily, J.W., Yoko, Y., Masayuki, Y., Misako, Y., Yohei, Y., Shigehiro, Y., Suzan, E.Z., Peter, G.Z., Xiaobei, Z., Silvia, Z., Kim, M.S., Harukazu, S., Carsten, O.D., Jun, K., Peter, H., Winston, H., Tom, C.F., Boris, L., Vladimir, B.B., Martin, S.T., Vsevolod, J.M., Albin, S., David, A.H., Piero, C., Yoshihide HayashizakiEhrlund, A., Mejhert, N., Itoh, M., Kawaji, H., Lassmann, T., Laurencikiene, J., Ryden, M., Arner, P., Hubrecht Institute for Developmental Biology and Stem Cell Research, AII - Amsterdam institute for Infection and Immunity, Infectious diseases, and Experimental Immunology

Subjects
Male, Angiogenesis, lcsh:Medicine, Adipose tissue, Gene Expression, Endocrinology, Neoplasms, Molecular Cell Biology, Basic Cancer Research, Databases, Genetic, Medicine and Health Sciences, Adipocytes, lcsh:Science, Multidisciplinary, biology, Cancer Risk Factors, Ceruloplasmin, Genomics, Middle Aged, Genomic Databases, Functional Genomics, Oncology, Adipose Tissue, Female, Transcriptome Analysis, Network Analysis, Research Article, Signal Transduction, Adult, medicine.medical_specialty, Computer and Information Sciences, Adipose tissue macrophages, Adipokine, Settore BIO/11 - Biologia Molecolare, Adipokines, Internal medicine, Cell Line, Tumor, medicine, Genetics, Cancer Genetics, Humans, Obesity, Sweden, business.industry, Gene Expression Profiling, lcsh:R, Cancer, Biology and Life Sciences, Computational Biology, Cell Biology, medicine.disease, Genome Analysis, Signaling Networks, Cell culture, Genetic Loci, Metabolic Disorders, Case-Control Studies, Cancer cell, biology.protein, lcsh:Q, business, Genome Expression Analysis
Abstract

Obesity confers an increased risk of developing specific cancer forms. Although the mechanisms are unclear, increased fat cell secretion of specific proteins (adipokines) may promote/facilitate development of malignant tumors in obesity via cross-talk between adipose tissue(s) and the tissues prone to develop cancer among obese. We searched for novel adipokines that were overexpressed in adipose tissue of obese subjects as well as in tumor cells derived from cancers commonly associated with obesity. For this purpose expression data from human adipose tissue of obese and non-obese as well as from a large panel of human cancer cell lines and corresponding primary cells and tissues were explored. We found expression of ceruloplasmin to be the most enriched in obesity-associated cancer cells. This gene was also significantly up-regulated in adipose tissue of obese subjects. Ceruloplasmin is the body's main copper carrier and is involved in angiogenesis. We demonstrate that ceruloplasmin is a novel adipokine, which is produced and secreted at increased rates in obesity. In the obese state, adipose tissue contributed markedly (up to 22%) to the total circulating protein level. In summary, we have through bioinformatic screening identified ceruloplasmin as a novel adipokine with increased expression in adipose tissue of obese subjects as well as in cells from obesity-associated cancers. Whether there is a causal relationship between adipose overexpression of ceruloplasmin and cancer development in obesity cannot be answered by these cross-sectional comparisons.

Published
2014

4. CCL2 enhances pluripotency of human induced pluripotent stem cells by activating hypoxia related genes

Author

Hasegawa, Y., Tang, D., Takahashi, N., Hayashizaki, Y., Forrest, A.R.R., Hideya, K., Michael, R., J Kenneth Baillie, Michiel J, L.D.H., Vanja, H., Timo, L., Ivan, V.K., Marina, L., Masayoshi, I., Robin, A., Christopher, J.M., Terrence, F.M., Sebastian, S., Nicolas, B., Mette, J., Emmanuel, D., Erik, A., Christian, S., Ulf, S., Yulia, A.M., Charles, P., Morana, V., Jessica, S., Colin, A.S., Yuri, I., Robert, S.Y., Margherita, F., Intikhab, A., Davide, A., Gabriel, M.A., Takahiro, A., John A, C.A., Peter, A., Magda, B., Sarah, B., Piotr, J.B., Anthony, G.B., Swati, P., Judith, A.B., Antje, B., Bodega, B., Alessandro, B., James, B., Frank, B., A Maxwell Burroughs, Andrea, C., Carlo, V.C., Daniel, C., Yun, C., Marco, C., Yari, C., Hans, C.C., Emiliano, D., Carrie, A.D., Michael, D., Alexander, D.D., Taeko, D., Finn, D., Albert S, B.E., Matthias, E., Karl, E., Mitsuhiro, E., Hideki, E., Michela, F., Lynsey, F., Hai, F., Mary, C.F., Geoffrey, J.F., Alexander, V.F., Malcolm, E.F., Martin, C.F., Rie, F., Shiro, F., Cesare, F., Masaaki, F., Jun-ichi, F., Teunis, B.G., Andrew, G., Thomas, G., Daniel, G., Julian, G., Sven, G., Reto, G., Stefano, G., Thomas, J.H., Masahide, H., Mitsuko, H., Matthias, H., Jayson, H., Akira, H., Yuki, H., Takehiro, H., Meenhard, H., Kelly, J.H., Shannan, J.H.S., Oliver, M.H., Ilka, H., Fumi, H., Lukasz, H., Kei, I., Tomokatsu, I., Boris, R.J., Hui, J., Anagha, J., Giuseppe, J., Bogumil, K., Chieko, K., Kaoru, K., Kaiho, A., Kazuhiro, K., Mutsumi, K., Artem, S.K., Takeya, K., Shintaro, K., Sachi, K., Shuji, K., Hiroshi, K., Yuki, I.K., Tsugumi, K., Judith, S.K., Tony, J.K., Juha, K., Levon, M.K., Toshio, K., S Peter Klinken, Alan, J.K., Miki, K., Soichi, K., Naoto, K., Haruhiko, K., Shigeo, K., Sarah, K., Atsutaka, K., Andrew, T.K., Jeroen F, J.L., Weonju, L., Andreas, L., Kang, L., Berit, L., Leonard, L., Alan, M., Ri-ichiroh, M., Jessica, C.M., Benoit, M., Anthony, M., Niklas, M., Alison, M., Yosuke, M., David, A.D.L.M., Hiromasa, M., Mitsuru, M., Kazuyo, M., Efthymios, M., Hozumi, M., Christine, L.M., Mitsuyoshi, M., Sayaka, N., Yutaka, N., Fumio, N., Toshiyuki, N., Yukio, N., Kenichi, N., Erik van Nimwegen, Noriko, N., Hiromi, N., Shohei, N., Tadasuke, N., Soichi, O., Naganari, O., Hiroko, O., Hiroshi, O., Mitsuhiro, O., Mariko, O., Yasushi, O., Valerio, O., Dmitry, A.O., Arnab, P., Robert, P., Margaret, P., Helena, P., Silvano, P., James G, D.P., Owen J, L.R., Jordan, A.R., Mamoon, R., Timothy, R., Patrizia, R., Marco, R., Sugata, R., Morten, B.R., Eri, S., Antti, S., Akiko, S., Shimon, S., Mizuho, S., Hiroki, S., Hironori, S., Suzana, S., Alka, S., Claudio, S., Erik, A.S., Gundula, G.S., Anita, S., Thierry, S., Guojun, S., Hisashi, S., Yishai, S., Jay, W.S., Christophe, S., Daisuke, S., Takaaki, S., Masanori, S., Naoko, S., Rolf, K.S., Peter A, C.'.H., Michihira, T., Naoko, T., Jun, T., Hiroshi, T., Hideki, T., Zuotian, T., Mark, T., Hiroo, T., Tetsuro, T., Eivind, V., Marc van de Wetering, Linda, M.V.D.B., Roberto, V., Dipti, V., Ilya, E.V., Wyeth, W.W., Shoko, W., Christine, A.W., Louise, N.W., Ernst, W., Emily, J.W., Yoko, Y., Masayuki, Y., Misako, Y., Yohei, Y., Shigehiro, Y., Suzan, E.Z., Peter, G.Z., Xiaobei, Z., Silvia, Z., Kim, M.S., Harukazu, S., Carsten, O.D., Jun, K., Peter, H., Winston, H., Tom, C.F., Boris, L., Vladimir, B.B., Martin, S.T., Vsevolod, J.M., Albin, S., David, A.H., Piero, C., Yoshihide HayashizakSuzuki, H., Hjelt Institute (-2014), Forensic Medicine, PaleOmics Laboratory, Amsterdam institute for Infection and Immunity, Infectious diseases, Experimental Immunology, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Stage-Specific Embryonic Antigens, Chromosomal Proteins, Non-Histone, Cellular differentiation, Basic fibroblast growth factor, Gene Expression, LINES, OXYGEN, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, Phosphorylation, STAT3, Induced pluripotent stem cell, Cells, Cultured, Chemokine CCL2, 0303 health sciences, Multidisciplinary, biology, Reverse Transcriptase Polymerase Chain Reaction, PROLIFERATION, Cell Differentiation, 319 Forensic science and other medical sciences, Nanog Homeobox Protein, Immunohistochemistry, Cell Hypoxia, Cell biology, HUMAN EMBRYONIC STEM, GROUND-STATE, Fibroblast Growth Factor 2, INACTIVATION, Signal transduction, Stem cell, Signal Transduction, Pluripotent Stem Cells, STAT3 Transcription Factor, EXPRESSION, Immunoblotting, Induced Pluripotent Stem Cells, Kruppel-Like Transcription Factors, Settore BIO/11 - Biologia Molecolare, Alkenes, Article, Kruppel-Like Factor 4, 03 medical and health sciences, Humans, Janus Kinases, 030304 developmental biology, Homeodomain Proteins, Proteins, Janus Kinase 1, CAP ANALYSIS, SELF-RENEWAL, chemistry, Epiblast, INDUCIBLE FACTOR-I, Immunology, biology.protein, 030217 neurology & neurosurgery
Abstract

Standard culture of human induced pluripotent stem cells (hiPSCs) requires basic Fibroblast Growth Factor (bFGF) to maintain the pluripotent state, whereas hiPSC more closely resemble epiblast stem cells than true naïve state ES which requires LIF to maintain pluripotency. Here we show that chemokine (C-C motif) ligand 2 (CCL2) enhances the expression of pluripotent marker genes through the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) protein. Moreover, comparison of transcriptomes between hiPSCs cultured with CCL2 versus with bFGF, we found that CCL2 activates hypoxia related genes, suggesting that CCL2 enhanced pluripotency by inducing a hypoxic-like response. Further, we show that hiPSCs cultured with CCL2 can differentiate at a higher efficiency than culturing with just bFGF and we show CCL2 can be used in feeder-free conditions in the absence of LIF. Taken together, our finding indicates the novel functions of CCL2 in enhancing its pluripotency in hiPSCs.

Published
2014
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5. Application of Gene Expression Trajectories Initiated from ErbB Receptor Activation Highlights the Dynamics of Divergent Promoter Usage

Author

Alistair R, R.F., Hideya, K., Michael, R., J Kenneth Baillie, Michiel J, L.D.H., Vanja, H., Timo, L., Ivan, V.K., Marina, L., Masayoshi, I., Robin, A., Christopher, J.M., Terrence, F.M., Sebastian, S., Nicolas, B., Mette, J., Emmanuel, D., Erik, A., Christian, S., Ulf, S., Yulia, A.M., Charles, P., Morana, V., Jessica, S., Colin, A.S., Yuri, I., Margherita, F., Intikhab, A., Davide, A., Gabriel, M.A., John A, C.A., Peter, A., Magda, B., Sarah, B., Piotr, J.B., Anthony, G.B., Swati, P., Judith, A.B., Antje, B., Bodega, B., Alessandro, B., James, B., Frank, B., A Maxwell Burroughs, Andrea, C., Carlo, V.C., Daniel, C., Yun, C., Marco, C., Yari, C., Hans, C.C., Emiliano, D., Carrie, A.D., Bart, D., Michael, D., Alexander, D.D., Taeko, D., Finn, D., Albert S, B.E., Matthias, E., Karl, E., Mitsuhiro, E., Hideki, E., Michela, F., Lynsey, F., Hai, F., Mary, C.F., Geoffrey, J.F., Alexander, V.F., Malcolm, E.F., Martin, C.F., Rie, F., Shiro, F., Cesare, F., Masaaki, F., Jun-ichi, F., Teunis, B.G., Andrew, G., Thomas, G., Daniel, G., Julian, G., Sven, G., Reto, G., Stefano, G., Thomas, J.H., Masahide, H., Mitsuko, H., Matthias, H., Jayson, H., Akira, H., Yuki, H., Takehiro, H., Meenhard, H., Kelly, J.H., Shannan, J.H.S., Oliver, M.H., Ilka, H., Fumi, H., Lukasz, H., Kei, I., Tomokatsu, I., Boris, R.J., Hui, J., Anagha, J., Giuseppe, J., Bogumil, K., Chieko, K., Kaoru, K., Kaiho, A., Kazuhiro, K., Mutsumi, K., Artem, S.K., Takeya, K., Shintaro, K., Sachi, K., Shuji, K., Hiroshi, K., Yuki, I.K., Tsugumi, K., Judith, S.K., Tony, J.K., Juha, K., Levon, M.K., Toshio, K., S Peter Klinken, Alan, J.K., Miki, K., Soichi, K., Naoto, K., Haruhiko, K., Shigeo, K., Sarah, K., Atsutaka, K., Andrew, T.K., Jeroen F, J.L., Weonju, L., Andreas, L., Kang, L., Berit, L., Leonard, L., Alan, M., Ri-ichiroh, M., Jessica, C.M., Benoit, M., Anthony, M., Niklas, M., Alison, M., Yosuke, M., David, A.D.L.M., Hiromasa, M., Mitsuru, M., Kazuyo, M., Efthymios, M., Hozumi, M., Christine, L.M., Mitsuyoshi, M., Sayaka, N., Yutaka, N., Fumio, N., Toshiyuki, N., Yukio, N., Kenichi, N., Erik van Nimwegen, Noriko, N., Hiromi, N., Shohei, N., Tadasuke, N., Soichi, O., Naganari, O., Hiroko, O., Hiroshi, O., Mitsuhiro, O., Mariko, O., Yasushi, O., Valerio, O., Dmitry, A.O., Arnab, P., Robert, P., Margaret, P., Helena, P., Silvano, P., James G, D.P., Owen J, L.R., Jordan, A.R., Mamoon, R., Timothy, R., Patrizia, R., Marco, R., Sugata, R., Morten, B.R., Eri, S., Antti, S., Akiko, S., Shimon, S., Mizuho, S., Hiroki, S., Hironori, S., Suzana, S., Alka, S., Claudio, S., Erik, A.S., Gundula, G.S., Anita, S., Thierry, S., Guojun, S., Hisashi, S., Yishai, S., Jay, W.S., Christophe, S., Daisuke, S., Takaaki, S., Masanori, S., Rolf, K.S., Peter A, C.'.H., Michihira, T., Naoko, T., Jun, T., Hiroshi, T., Hideki, T., Zuotian, T., Mark, T., Hiroo, T., Tetsuro, T., Eivind, V., Marc van de Wetering, Linda, M.V.D.B., Roberto, V., Dipti, V., Ilya, E.V., Wyeth, W.W., Shoko, W., Christine, A.W., Louise, N.W., Ernst, W., Emily, J.W., Yoko, Y., Masayuki, Y., Misako, Y., Yohei, Y., Shigehiro, Y., Suzan, E.Z., Peter, G.Z., Xiaobei, Z., Silvia, Z., Kim, M.S., Harukazu, S., Carsten, O.D., Jun, K., Peter, H., Winston, H., Tom, C.F., Boris, L., Vladimir, B.B., Martin, S.T., Vsevolod, J.M., Albin, S., David, A.H., Piero, C., Yoshihide Hayashizaki Carbajo, D., Magi, S., Itoh, M., Kawaji, H., Lassmann, T., Arner, E., Forrest, A.R.R., Carninci, P., Hayashizaki, Y., Daub, C.O., Okada-Hatakeyama, M., Mar, J.C., Hubrecht Institute for Developmental Biology and Stem Cell Research, Amsterdam institute for Infection and Immunity, Infectious diseases, and Experimental Immunology

Subjects
MAP Kinase Signaling System, Neuregulin-1, Cellular differentiation, lcsh:Medicine, Gene Expression, Settore BIO/11 - Biologia Molecolare, Apoptosis, Breast Neoplasms, Cell fate determination, Biology, Cell Line, Promoter Regions, Genetic, Cell Line, Tumor, Humans, Cell Cycle, Cell Differentiation, Cell Proliferation, Enzyme Activation, Epidermal Growth Factor, ErbB Receptors, Extracellular Signal-Regulated MAP Kinases, Female, Focal Adhesions, Gene Expression Profiling, Gene Expression Regulation, MCF-7 Cells, Promoter Regions, Genetic, Tumor Suppressor Protein p53, lcsh:Science, Transcription factor, Genetics, Regulation of gene expression, Tumor, Multidisciplinary, lcsh:R, Promoter, FHL2, Cell biology, Gene expression profiling, lcsh:Q, Signal transduction, Research Article
Abstract

Understanding how cells use complex transcriptional programs to alter their fate in response to specific stimuli is an important question in biology. For the MCF-7 human breast cancer cell line, we applied gene expression trajectory models to identify the genes involved in driving cell fate transitions. We modified trajectory models to account for the scenario where cells were exposed to different stimuli, in this case epidermal growth factor and heregulin, to arrive at different cell fates, i.e. proliferation and differentiation respectively. Using genome-wide CAGE time series data collected from the FANTOM5 consortium, we identified the sets of promoters that were involved in the transition of MCF-7 cells to their specific fates versus those with expression changes that were generic to both stimuli. Of the 1,552 promoters identified, 1,091 had stimulus-specific expression while 461 promoters had generic expression profiles over the time course surveyed. Many of these stimulus-specific promoters mapped to key regulators of the ERK (extracellular signal-regulated kinases) signaling pathway such as FHL2 (four and a half LIM domains 2). We observed that in general, generic promoters peaked in their expression early on in the time course, while stimulus-specific promoters tended to show activation of their expression at a later stage. The genes that mapped to stimulus-specific promoters were enriched for pathways that control focal adhesion, p53 signaling and MAPK signaling while generic promoters were enriched for cell death, transcription and the cell cycle. We identified 162 genes that were controlled by an alternative promoter during the time course where a subset of 37 genes had separate promoters that were classified as stimulus-specific and generic. The results of our study highlighted the degree of complexity involved in regulating a cell fate transition where multiple promoters mapping to the same gene can demonstrate quite divergent expression profiles.

Published
2015
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