The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line
Hideya Kawaji(RIKEN Center for Integrative Medical Sciences), Norihiro Maeda(Griffith University), Takehiro Hashimoto(University of Basel), Kayoko Murakami(RIKEN Center for Integrative Medical Sciences), Andreas Lennartsson(University of Basel), Timo Lassmann(The University of Queensland), Kazumi Yamaguchi(RIKEN Center for Integrative Medical Sciences), Shohei Noma(University of California San Diego), Yayoi Kitazume(RIKEN Center for Integrative Medical Sciences), Noriko Ninomiya(RIKEN Center for Integrative Medical Sciences), Yasuhiro Tomaru(RIKEN Center for Integrative Medical Sciences), Ryoko Ishihara(The University of Queensland), Chika Kawazu(RIKEN Center for Integrative Medical Sciences), Shiro Fukuda(RIKEN Center for Integrative Medical Sciences), Nicolas Bertin(RIKEN Center for Integrative Medical Sciences), Takahiro Suzuki(RIKEN Center for Integrative Medical Sciences), Mika Nakano(RIKEN Center for Integrative Medical Sciences), Chikatoshi Kai(RIKEN Center for Integrative Medical Sciences), Tsugumi Kawashima(RIKEN Center for Integrative Medical Sciences), Y. Hayashizaki(RIKEN Center for Integrative Medical Sciences), Chihiro Ogawa(RIKEN Center for Integrative Medical Sciences), Yuki Hasegawa(The University of Queensland), Carsten O. Daub(RIKEN Center for Integrative Medical Sciences), Jessica Severin(The University of Queensland), Takuma Sano(Griffith University), Kazunori Waki(RIKEN Center for Integrative Medical Sciences), Mutsumi Kanamori-Katayama(Karolinska Institutet), Harukazu Suzuki(University of Cape Town), Alistair R R Forrest(Griffith University), Shintaro Katayama(Griffith University), Yukari Takahashi(Tokyo University of Science), Hiromi Nishiyori(The University of Queensland), Masaaki Furuno(RIKEN Center for Integrative Medical Sciences), Andrew Waterhouse(RIKEN Center for Integrative Medical Sciences), Haruka Okuda-Yabukami(RIKEN Center for Integrative Medical Sciences), Miki Kojima(RIKEN Center for Integrative Medical Sciences), Charles Plessy(The University of Queensland), Erika Bulger(The University of Queensland), Erik Arner(RIKEN Center for Integrative Medical Sciences), Shinji Kondo(RIKEN Center for Integrative Medical Sciences), Mitsuyoshi Murata(RIKEN Center for Integrative Medical Sciences), Michihira Tagami(RIKEN Center for Integrative Medical Sciences), Michiel de Hoon(University of Bristol), Yoshinari Ando(The University of Queensland), Jun Yasuda(Linköping University), Hisashi Miura(RIKEN Center for Integrative Medical Sciences), Atsutaka Kubosaki(RIKEN Center for Integrative Medical Sciences), Piero Carninci(RIKEN Center for Integrative Medical Sciences), Christophe Simon(Flinders University), Jun Kawai(Harvard University Press), Kengo Imamura(Harvard University Press), Masanori Suzuki(Linköping University), Takahiro Arakawa(Karolinska Institutet), Yasumasa Kimura(RIKEN Center for Integrative Medical Sciences), Marina Lizio(RIKEN Center for Integrative Medical Sciences), Ai Kaiho(RIKEN Center for Integrative Medical Sciences), Christine A. Wells(Griffith University), Alistair M. Chalk(Griffith University), Anthony G Beckhouse(Griffith University), Alistair R R Forrest(Griffith University), Nicholas Matigian(Griffith University), Piotr J. Balwierz(SIB Swiss Institute of Bioinformatics), Mihaela Zavolan(SIB Swiss Institute of Bioinformatics), Erik van Nimwegen(SIB Swiss Institute of Bioinformatics), Mikhail Pachkov(SIB Swiss Institute of Bioinformatics), Katharine M. Irvine(The University of Queensland), Kate Schroder(The University of Queensland), Timothy L. Bailey(The University of Queensland), Denis C. Bauer(The University of Queensland), Timothy Ravasi(University of California San Diego), Ariel Schwartz(University of California San Diego), Kai Tan(University of Copenhagen), Altuna Akalin(University of Bergen), Pär G. Engström(George Washington University), Boris Lenhard(University of Bergen), David Fredman(University of Bergen), Megumi Hashimoto(University of Copenhagen), Maki Asada(National Center For Child Health and Development), Hiroshi Asahara(National Center For Child Health and Development), Magbubah Essack(University of the Western Cape), Adam Dawe(University of the Western Cape), Vladimir B. Bajić(University of the Western Cape), Adéle Kruger(Harvard University Press), Aleksandar Radovanović(Griffith University), Mandeep Kaur(University of the Western Cape), Cameron Ross MacPherson(The University of Queensland), Monique Maqungo(University of the Western Cape), Christopher A. Maher(University of the Western Cape), Winston Hide(Harvard University), Oliver Hofmann(Harvard University), Stuart Meier(Saitama Medical University), Sebastian Schmeier(University of the Western Cape), Johan Björkegren(University of Copenhagen), Jesper Tegnér(Linköping University), Frank Brombacher(University of Cape Town), Joe Chiba(Tokyo University of Science), Kazuhiko Nakabayashi(Tokyo University of Science), Ryuichiro Kimura(Tokyo University of Science), Ryan J. Taft(Australian Research Council), Sean M. Grimmond(Australian Research Council), John S. Mattick(Australian Research Council), Geoffrey J. Faulkner(Australian Research Council), Cas Simons(Australian Research Council), Nicole Cloonan(Australian Research Council), Josée Dostie(Keio University), J. Lynn Fink(University of Copenhagen), Markus C. Kerr(Australian Research Council), Rohan D. Teasdale(Australian Research Council), Ko Fujimori(University of California San Diego), T. Konno(Research Organization of Information and Systems), Takashi Gojobori(Research Organization of Information and Systems), Toshitsugu Okayama(Research Organization of Information and Systems), Sei Miyamoto(Tokyo Institute of Technology), Miho Sera(The University of Queensland), Kazuho Ikeo(George Washington University), Julian Gough(University of Bristol), Michael Hörnquist(Linköping University), Mika Gustafsson(Linköping University), Mariko Hatakeyama(The University of Queensland), Toshio Kojima(RIKEN Center for Integrative Medical Sciences), Linda Wu(Flinders Medical Centre), Susanne Heinzel(Flinders Medical Centre), Nikolai Petrovsky(Flinders Medical Centre), Oliver Hofmann(Harvard University), Winston Hide (Linköping University), Łukasz Huminiecki(Karolinska Institutet), Naoko Imamoto(University of Copenhagen), Satoshi Inoue(Scripps Research Institute), Yusuke Inoue(Gunma University), Takao Iwayanagi(Hitachi (Japan)), Albin Sandelin(Griffith University), Ole Winther(University of Copenhagen), Anders Jacobsen(University of Copenhagen), Sanne Nygaard(University of Copenhagen), Anders Krogh(University of Copenhagen), Eivind Valen(University of Copenhagen), Morten Lindow(University of Copenhagen), Syuhei Kimura(Tottori University), Hiroaki Kitano(Systems Biology Institute), Hisashi Koga(Kazusa DNA Research Institute), George St. Laurent(Washington University Medical Center), Ajit Kumar(Washington University Medical Center), Jessica C. Mar(Dana-Farber Cancer Institute), John Quackenbush(Dana-Farber Cancer Institute), Yoichi Takenaka(The University of Osaka), Hideo Matsuda(The University of Osaka), Hiroshi Yanagawa(Keio University), Etsuko Miyamoto‐Sato(Keio University), Yutaka Nakachi(Saitama Medical University), Yasushi Okazaki(Saitama Medical University), Valerio Orlando(Dulbecco Telethon Institute), Jun Otomo(Hitachi (Japan)), Shizu Takeda(Hitachi (Japan)), Michael Rehli(University Hospital Regensburg), Rintaro Saito(Keio University Shonan Fujisawa), Christian Schönbach(Nanyang Technological University), Colin A. Semple(Western General Hospital), Katsuhiko Shirahige(Tokyo Institute of Technology), Matthew J. Sweet(The University of Queensland), Martin S. Taylor(European Bioinformatics Institute), Jesper Tegnér(Linköping University), Sarah A. Teichmann(MRC Laboratory of Molecular Biology), Claes Wahlestedt(Scripps Research Institute), David Hume(Roslin Institute)
Cited by 430Open Access
Abstract
The FANTOM4 study identified transcriptional start sites active during proliferation arrest and differentiation of the human monocytic cell line THP-1. Systematic knockdown of 52 transcription factors provide support for their model in which a complex transcriptional network regulates the differentiation process. Using deep sequencing (deepCAGE), the FANTOM4 study measured the genome-wide dynamics of transcription-start-site usage in the human monocytic cell line THP-1 throughout a time course of growth arrest and differentiation. Modeling the expression dynamics in terms of predicted cis-regulatory sites, we identified the key transcription regulators, their time-dependent activities and target genes. Systematic siRNA knockdown of 52 transcription factors confirmed the roles of individual factors in the regulatory network. Our results indicate that cellular states are constrained by complex networks involving both positive and negative regulatory interactions among substantial numbers of transcription factors and that no single transcription factor is both necessary and sufficient to drive the differentiation process.
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