Trans-omics analysis of insulin action reveals a cell growth subnetwork which co-regulates anabolic processes
Akira Terakawa,
Yanhui Hu,
Toshiya Kokaji,
Katsuyuki Yugi,
Keigo Morita,
Satoshi Ohno,
Yifei Pan,
Yunfan Bai,
Andrey A. Parkhitko,
Xiaochun Ni,
John M. Asara,
Martha L. Bulyk,
Norbert Perrimon,
Shinya Kuroda
Affiliations
Akira Terakawa
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Yanhui Hu
Department of Genetics, Blavatnik Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Drosophila RNAi Screening Center, Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
Toshiya Kokaji
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Data Science Center, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara, Japan
Katsuyuki Yugi
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Institute for Advanced Biosciences, Keio University, Fujisawa, 252-8520, Japan
Keigo Morita
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Satoshi Ohno
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
Yifei Pan
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
Yunfan Bai
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
Andrey A. Parkhitko
Department of Genetics, Blavatnik Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, PA, USA
Xiaochun Ni
Department of Genetics, Blavatnik Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
John M. Asara
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02175, USA
Martha L. Bulyk
Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham & Women’s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
Norbert Perrimon
Department of Genetics, Blavatnik Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Corresponding author
Shinya Kuroda
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan; Corresponding author
Summary: Insulin signaling promotes anabolic metabolism to regulate cell growth through multi-omic interactions. To obtain a comprehensive view of the cellular responses to insulin, we constructed a trans-omic network of insulin action in Drosophila cells that involves the integration of multi-omic data sets. In this network, 14 transcription factors, including Myc, coordinately upregulate the gene expression of anabolic processes such as nucleotide synthesis, transcription, and translation, consistent with decreases in metabolites such as nucleotide triphosphates and proteinogenic amino acids required for transcription and translation. Next, as cell growth is required for cell proliferation and insulin can stimulate proliferation in a context-dependent manner, we integrated the trans-omic network with results from a CRISPR functional screen for cell proliferation. This analysis validates the role of a Myc-mediated subnetwork that coordinates the activation of genes involved in anabolic processes required for cell growth.
