The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line

Harukazu Suzuki; Alistair R.R. Forrest; Erik Van Nimwegen; Carsten O. Daub; Piotr J. Balwierz; Katharine M. Irvine; Timo Lassmann; Timothy Ravasi; Yuki Hasegawa; Michiel J.L. De Hoon; Shintaro Katayama; Kate Schroder; Piero Carninci; Yasuhiro Tomaru; Mutsumi Kanamori-Katayama; Atsutaka Kubosaki; Altuna Akalin; Yoshinari Ando; Erik Arner; Maki Asada; Hiroshi Asahara; Timothy Bailey; Vladimir B. Bajic; Denis Bauer; Anthony G. Beckhouse; Nicolas Bertin; Johan Björkegren; Frank Brombacher; Erika Bulger; Alistair M. Chalk; Joe Chiba; Nicole Cloonan; Adam Dawe; Josee Dostie; Pär G. Engström; Magbubah Essack; Geoffrey J. Faulkner; J. Lynn Fink; David Fredman; Ko Fujimori; Masaaki Furuno; Takashi Gojobori; Julian Gough; Sean M. Grimmond; Mika Gustafsson; Megumi Hashimoto; Takehiro Hashimoto; Mariko Hatakeyama; Susanne Heinzel; Winston Hide; Oliver Hofmann; Michael Hörnquist; Lukasz Huminiecki; Kazuho Ikeo; Naoko Imamoto; Satoshi Inoue; Yusuke Inoue; Ryoko Ishihara; Takao Iwayanagi; Anders Jacobsen; Mandeep Kaur; Hideya Kawaji; Markus C. Kerr; Ryuichiro Kimura; Syuhei Kimura; Yasumasa Kimura; Hiroaki Kitano; Hisashi Koga; Toshio Kojima; Shinji Kondo; Takeshi Konno; Anders Krogh; Adele Kruger; Ajit Kumar; Boris Lenhard; Andreas Lennartsson; Morten Lindow; Marina Lizio; Cameron MacPherson; Norihiro Maeda; Christopher A. Maher; Monique Maqungo; Jessica Mar; Nicholas A. Matigian; Hideo Matsuda; John S. Mattick; Stuart Meier; Sei Miyamoto; Etsuko Miyamoto-Sato; Kazuhiko Nakabayashi; Yutaka Nakachi; Mika Nakano; Sanne Nygaard; Toshitsugu Okayama; Yasushi Okazaki; Haruka Okuda-Yabukami; Valerio Orlando; Jun Otomo; Mikhail Pachkov; Nikolai Petrovsky; Charles Plessy; John Quackenbush; Aleksandar Radovanovic; Michael Rehli; Rintaro Saito; Albin Sandelin; Sebastian Schmeier; Christian Schönbach; Ariel S. Schwartz; Colin A. Semple; Miho Sera; Jessica Severin; Katsuhiko Shirahige; Cas Simons; George St. Laurent; Masanori Suzuki; Takahiro Suzuki; Matthew J. Sweet; Ryan J. Taft; Shizu Takeda; Yoichi Takenaka; Kai Tan; Martin S. Taylor; Rohan D. Teasdale; Jesper Tegnér; Sarah Teichmann; Eivind Valen; Claes Wahlestedt; Kazunori Waki; Andrew Waterhouse; Christine A. Wells; Ole Winther; Linda Wu; Kazumi Yamaguchi; Hiroshi Yanagawa; Jun Yasuda; Mihaela Zavolan; David A. Hume; Takahiro Arakawa; Shiro Fukuda; Kengo Imamura; Chikatoshi Kai; Ai Kaiho; Tsugumi Kawashima; Chika Kawazu; Yayoi Kitazume; Miki Kojima; Hisashi Miura; Kayoko Murakami; Mitsuyoshi Murata; Noriko Ninomiya; Hiromi Nishiyori; Shohei Noma; Chihiro Ogawa; Takuma Sano; Christophe Simon; Michihira Tagami; Yukari Takahashi; Jun Kawai; Yoshihide Hayashizaki

doi:10.1038/ng.375

The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line

Harukazu Suzuki, Alistair R.R. Forrest, Erik Van Nimwegen, Carsten O. Daub, Piotr J. Balwierz, Katharine M. Irvine, Timo Lassmann, Timothy Ravasi, Yuki Hasegawa, Michiel J.L. De Hoon, Shintaro Katayama, Kate Schroder, Piero Carninci, Yasuhiro Tomaru, Mutsumi Kanamori-Katayama, Atsutaka Kubosaki, Altuna Akalin, Yoshinari Ando, Erik Arner, Maki AsadaHiroshi Asahara, Timothy Bailey, Vladimir B. Bajic, Denis Bauer, Anthony G. Beckhouse, Nicolas Bertin, Johan Björkegren, Frank Brombacher, Erika Bulger, Alistair M. Chalk, Joe Chiba, Nicole Cloonan, Adam Dawe, Josee Dostie, Pär G. Engström, Magbubah Essack, Geoffrey J. Faulkner, J. Lynn Fink, David Fredman, Ko Fujimori, Masaaki Furuno, Takashi Gojobori, Julian Gough, Sean M. Grimmond, Mika Gustafsson, Megumi Hashimoto, Takehiro Hashimoto, Mariko Hatakeyama, Susanne Heinzel, Winston Hide, Oliver Hofmann, Michael Hörnquist, Lukasz Huminiecki, Kazuho Ikeo, Naoko Imamoto, Satoshi Inoue, Yusuke Inoue, Ryoko Ishihara, Takao Iwayanagi, Anders Jacobsen, Mandeep Kaur, Hideya Kawaji, Markus C. Kerr, Ryuichiro Kimura, Syuhei Kimura, Yasumasa Kimura, Hiroaki Kitano, Hisashi Koga, Toshio Kojima, Shinji Kondo, Takeshi Konno, Anders Krogh, Adele Kruger, Ajit Kumar, Boris Lenhard, Andreas Lennartsson, Morten Lindow, Marina Lizio, Cameron MacPherson, Norihiro Maeda, Christopher A. Maher, Monique Maqungo, Jessica Mar, Nicholas A. Matigian, Hideo Matsuda, John S. Mattick, Stuart Meier, Sei Miyamoto, Etsuko Miyamoto-Sato, Kazuhiko Nakabayashi, Yutaka Nakachi, Mika Nakano, Sanne Nygaard, Toshitsugu Okayama, Yasushi Okazaki, Haruka Okuda-Yabukami, Valerio Orlando, Jun Otomo, Mikhail Pachkov, Nikolai Petrovsky, Charles Plessy, John Quackenbush, Aleksandar Radovanovic, Michael Rehli, Rintaro Saito, Albin Sandelin, Sebastian Schmeier, Christian Schönbach, Ariel S. Schwartz, Colin A. Semple, Miho Sera, Jessica Severin, Katsuhiko Shirahige, Cas Simons, George St. Laurent, Masanori Suzuki, Takahiro Suzuki, Matthew J. Sweet, Ryan J. Taft, Shizu Takeda, Yoichi Takenaka, Kai Tan, Martin S. Taylor, Rohan D. Teasdale, Jesper Tegnér, Sarah Teichmann, Eivind Valen, Claes Wahlestedt, Kazunori Waki, Andrew Waterhouse, Christine A. Wells, Ole Winther, Linda Wu, Kazumi Yamaguchi, Hiroshi Yanagawa, Jun Yasuda, Mihaela Zavolan, David A. Hume, Takahiro Arakawa, Shiro Fukuda, Kengo Imamura, Chikatoshi Kai, Ai Kaiho, Tsugumi Kawashima, Chika Kawazu, Yayoi Kitazume, Miki Kojima, Hisashi Miura, Kayoko Murakami, Mitsuyoshi Murata, Noriko Ninomiya, Hiromi Nishiyori, Shohei Noma, Chihiro Ogawa, Takuma Sano, Christophe Simon, Michihira Tagami, Yukari Takahashi, Jun Kawai, Yoshihide Hayashizaki

Research output: Contribution to journal › Article › peer-review

358 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	553-562
Number of pages	10
Journal	Nature Genetics
Volume	41
Issue number	5
DOIs	https://doi.org/10.1038/ng.375
State	Published - May 2009
Externally published	Yes

ASJC Scopus subject areas

Genetics

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10.1038/ng.375

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Suzuki, H., Forrest, A. R. R., Van Nimwegen, E., Daub, C. O., Balwierz, P. J., Irvine, K. M., Lassmann, T., Ravasi, T., Hasegawa, Y., De Hoon, M. J. L., Katayama, S., Schroder, K., Carninci, P., Tomaru, Y., Kanamori-Katayama, M., Kubosaki, A., Akalin, A., Ando, Y., Arner, E., ... Hayashizaki, Y. (2009). The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line. Nature Genetics, 41(5), 553-562. https://doi.org/10.1038/ng.375

Suzuki, H, Forrest, ARR, Van Nimwegen, E, Daub, CO, Balwierz, PJ, Irvine, KM, Lassmann, T, Ravasi, T, Hasegawa, Y, De Hoon, MJL, Katayama, S, Schroder, K, Carninci, P, Tomaru, Y, Kanamori-Katayama, M, Kubosaki, A, Akalin, A, Ando, Y, Arner, E, Asada, M, Asahara, H, Bailey, T, Bajic, VB, Bauer, D, Beckhouse, AG, Bertin, N, Björkegren, J, Brombacher, F, Bulger, E, Chalk, AM, Chiba, J, Cloonan, N, Dawe, A, Dostie, J, Engström, PG, Essack, M, Faulkner, GJ, Fink, JL, Fredman, D, Fujimori, K, Furuno, M, Gojobori, T, Gough, J, Grimmond, SM, Gustafsson, M, Hashimoto, M, Hashimoto, T, Hatakeyama, M, Heinzel, S, Hide, W, Hofmann, O, Hörnquist, M, Huminiecki, L, Ikeo, K, Imamoto, N, Inoue, S, Inoue, Y, Ishihara, R, Iwayanagi, T, Jacobsen, A, Kaur, M, Kawaji, H, Kerr, MC, Kimura, R, Kimura, S, Kimura, Y, Kitano, H, Koga, H, Kojima, T, Kondo, S, Konno, T, Krogh, A, Kruger, A, Kumar, A, Lenhard, B, Lennartsson, A, Lindow, M, Lizio, M, MacPherson, C, Maeda, N, Maher, CA, Maqungo, M, Mar, J, Matigian, NA, Matsuda, H, Mattick, JS, Meier, S, Miyamoto, S, Miyamoto-Sato, E, Nakabayashi, K, Nakachi, Y, Nakano, M, Nygaard, S, Okayama, T, Okazaki, Y, Okuda-Yabukami, H, Orlando, V, Otomo, J, Pachkov, M, Petrovsky, N, Plessy, C, Quackenbush, J, Radovanovic, A, Rehli, M, Saito, R, Sandelin, A, Schmeier, S, Schönbach, C, Schwartz, AS, Semple, CA, Sera, M, Severin, J, Shirahige, K, Simons, C, St. Laurent, G, Suzuki, M, Suzuki, T, Sweet, MJ, Taft, RJ, Takeda, S, Takenaka, Y, Tan, K, Taylor, MS, Teasdale, RD, Tegnér, J, Teichmann, S, Valen, E, Wahlestedt, C, Waki, K, Waterhouse, A, Wells, CA, Winther, O, Wu, L, Yamaguchi, K, Yanagawa, H, Yasuda, J, Zavolan, M, Hume, DA, Arakawa, T, Fukuda, S, Imamura, K, Kai, C, Kaiho, A, Kawashima, T, Kawazu, C, Kitazume, Y, Kojima, M, Miura, H, Murakami, K, Murata, M, Ninomiya, N, Nishiyori, H, Noma, S, Ogawa, C, Sano, T, Simon, C, Tagami, M, Takahashi, Y, Kawai, J & Hayashizaki, Y 2009, 'The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line', Nature Genetics, vol. 41, no. 5, pp. 553-562. https://doi.org/10.1038/ng.375

@article{50fe61df237f40bb9056ae313aaf496d,

title = "The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line",

abstract = "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.",

author = "Harukazu Suzuki and Forrest, {Alistair R.R.} and {Van Nimwegen}, Erik and Daub, {Carsten O.} and Balwierz, {Piotr J.} and Irvine, {Katharine M.} and Timo Lassmann and Timothy Ravasi and Yuki Hasegawa and {De Hoon}, {Michiel J.L.} and Shintaro Katayama and Kate Schroder and Piero Carninci and Yasuhiro Tomaru and Mutsumi Kanamori-Katayama and Atsutaka Kubosaki and Altuna Akalin and Yoshinari Ando and Erik Arner and Maki Asada and Hiroshi Asahara and Timothy Bailey and Bajic, {Vladimir B.} and Denis Bauer and Beckhouse, {Anthony G.} and Nicolas Bertin and Johan Bj{\"o}rkegren and Frank Brombacher and Erika Bulger and Chalk, {Alistair M.} and Joe Chiba and Nicole Cloonan and Adam Dawe and Josee Dostie and Engstr{\"o}m, {P{\"a}r G.} and Magbubah Essack and Faulkner, {Geoffrey J.} and Fink, {J. Lynn} and David Fredman and Ko Fujimori and Masaaki Furuno and Takashi Gojobori and Julian Gough and Grimmond, {Sean M.} and Mika Gustafsson and Megumi Hashimoto and Takehiro Hashimoto and Mariko Hatakeyama and Susanne Heinzel and Winston Hide and Oliver Hofmann and Michael H{\"o}rnquist and Lukasz Huminiecki and Kazuho Ikeo and Naoko Imamoto and Satoshi Inoue and Yusuke Inoue and Ryoko Ishihara and Takao Iwayanagi and Anders Jacobsen and Mandeep Kaur and Hideya Kawaji and Kerr, {Markus C.} and Ryuichiro Kimura and Syuhei Kimura and Yasumasa Kimura and Hiroaki Kitano and Hisashi Koga and Toshio Kojima and Shinji Kondo and Takeshi Konno and Anders Krogh and Adele Kruger and Ajit Kumar and Boris Lenhard and Andreas Lennartsson and Morten Lindow and Marina Lizio and Cameron MacPherson and Norihiro Maeda and Maher, {Christopher A.} and Monique Maqungo and Jessica Mar and Matigian, {Nicholas A.} and Hideo Matsuda and Mattick, {John S.} and Stuart Meier and Sei Miyamoto and Etsuko Miyamoto-Sato and Kazuhiko Nakabayashi and Yutaka Nakachi and Mika Nakano and Sanne Nygaard and Toshitsugu Okayama and Yasushi Okazaki and Haruka Okuda-Yabukami and Valerio Orlando and Jun Otomo and Mikhail Pachkov and Nikolai Petrovsky and Charles Plessy and John Quackenbush and Aleksandar Radovanovic and Michael Rehli and Rintaro Saito and Albin Sandelin and Sebastian Schmeier and Christian Sch{\"o}nbach and Schwartz, {Ariel S.} and Semple, {Colin A.} and Miho Sera and Jessica Severin and Katsuhiko Shirahige and Cas Simons and {St. Laurent}, George and Masanori Suzuki and Takahiro Suzuki and Sweet, {Matthew J.} and Taft, {Ryan J.} and Shizu Takeda and Yoichi Takenaka and Kai Tan and Taylor, {Martin S.} and Teasdale, {Rohan D.} and Jesper Tegn{\'e}r and Sarah Teichmann and Eivind Valen and Claes Wahlestedt and Kazunori Waki and Andrew Waterhouse and Wells, {Christine A.} and Ole Winther and Linda Wu and Kazumi Yamaguchi and Hiroshi Yanagawa and Jun Yasuda and Mihaela Zavolan and Hume, {David A.} and Takahiro Arakawa and Shiro Fukuda and Kengo Imamura and Chikatoshi Kai and Ai Kaiho and Tsugumi Kawashima and Chika Kawazu and Yayoi Kitazume and Miki Kojima and Hisashi Miura and Kayoko Murakami and Mitsuyoshi Murata and Noriko Ninomiya and Hiromi Nishiyori and Shohei Noma and Chihiro Ogawa and Takuma Sano and Christophe Simon and Michihira Tagami and Yukari Takahashi and Jun Kawai and Yoshihide Hayashizaki",

note = "Funding Information: We thank A. Ambesi, H. Atsui, M. Bansal, V. Belcastro, H. Daub, D. di Bernardo, M. Furuya, A. Hasegawa, K. Hayashida, A. Hirakiyama, F. Hori, K. Koseki, S. Kuhara, N. Miyamoto, S. Miyano, M. Nishikawa, C. Ohinata, M. Persson, S. Saihara, C. Sakaba, H. Sano, E. Shibazaki, T. Takagi, K. Toyoda, Y. Tsujimura and M. Yamamoto for discussion, encouragement and technical assistance. We thank M. Muramatsu, T. Ogawa, Y. Sakaki and A. Wada for support and encouragement. This work was mainly supported by grants for the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan (Y.H.), Research Grant for the RIKEN Genome Exploration Research Project from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (Y.H.) and the RIKEN Frontier Research System, Functional RNA research program (Y.H.). A.R.R.F. is supported by a CJ Martin Fellowship from the Australian National Health and Medical Research Council (ID 428261). E.v.N. acknowledges support from SNF grant SNF #3100A0-118318.",

year = "2009",

month = may,

doi = "10.1038/ng.375",

language = "English (US)",

volume = "41",

pages = "553--562",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

}

TY - JOUR

T1 - The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line

AU - Suzuki, Harukazu

AU - Forrest, Alistair R.R.

AU - Van Nimwegen, Erik

AU - Daub, Carsten O.

AU - Balwierz, Piotr J.

AU - Irvine, Katharine M.

AU - Lassmann, Timo

AU - Ravasi, Timothy

AU - Hasegawa, Yuki

AU - De Hoon, Michiel J.L.

AU - Katayama, Shintaro

AU - Schroder, Kate

AU - Carninci, Piero

AU - Tomaru, Yasuhiro

AU - Kanamori-Katayama, Mutsumi

AU - Kubosaki, Atsutaka

AU - Akalin, Altuna

AU - Ando, Yoshinari

AU - Arner, Erik

AU - Asada, Maki

AU - Asahara, Hiroshi

AU - Bailey, Timothy

AU - Bajic, Vladimir B.

AU - Bauer, Denis

AU - Beckhouse, Anthony G.

AU - Bertin, Nicolas

AU - Björkegren, Johan

AU - Brombacher, Frank

AU - Bulger, Erika

AU - Chalk, Alistair M.

AU - Chiba, Joe

AU - Cloonan, Nicole

AU - Dawe, Adam

AU - Dostie, Josee

AU - Engström, Pär G.

AU - Essack, Magbubah

AU - Faulkner, Geoffrey J.

AU - Fink, J. Lynn

AU - Fredman, David

AU - Fujimori, Ko

AU - Furuno, Masaaki

AU - Gojobori, Takashi

AU - Gough, Julian

AU - Grimmond, Sean M.

AU - Gustafsson, Mika

AU - Hashimoto, Megumi

AU - Hashimoto, Takehiro

AU - Hatakeyama, Mariko

AU - Heinzel, Susanne

AU - Hide, Winston

AU - Hofmann, Oliver

AU - Hörnquist, Michael

AU - Huminiecki, Lukasz

AU - Ikeo, Kazuho

AU - Imamoto, Naoko

AU - Inoue, Satoshi

AU - Inoue, Yusuke

AU - Ishihara, Ryoko

AU - Iwayanagi, Takao

AU - Jacobsen, Anders

AU - Kaur, Mandeep

AU - Kawaji, Hideya

AU - Kerr, Markus C.

AU - Kimura, Ryuichiro

AU - Kimura, Syuhei

AU - Kimura, Yasumasa

AU - Kitano, Hiroaki

AU - Koga, Hisashi

AU - Kojima, Toshio

AU - Kondo, Shinji

AU - Konno, Takeshi

AU - Krogh, Anders

AU - Kruger, Adele

AU - Kumar, Ajit

AU - Lenhard, Boris

AU - Lennartsson, Andreas

AU - Lindow, Morten

AU - Lizio, Marina

AU - MacPherson, Cameron

AU - Maeda, Norihiro

AU - Maher, Christopher A.

AU - Maqungo, Monique

AU - Mar, Jessica

AU - Matigian, Nicholas A.

AU - Matsuda, Hideo

AU - Mattick, John S.

AU - Meier, Stuart

AU - Miyamoto, Sei

AU - Miyamoto-Sato, Etsuko

AU - Nakabayashi, Kazuhiko

AU - Nakachi, Yutaka

AU - Nakano, Mika

AU - Nygaard, Sanne

AU - Okayama, Toshitsugu

AU - Okazaki, Yasushi

AU - Okuda-Yabukami, Haruka

AU - Orlando, Valerio

AU - Otomo, Jun

AU - Pachkov, Mikhail

AU - Petrovsky, Nikolai

AU - Plessy, Charles

AU - Quackenbush, John

AU - Radovanovic, Aleksandar

AU - Rehli, Michael

AU - Saito, Rintaro

AU - Sandelin, Albin

AU - Schmeier, Sebastian

AU - Schönbach, Christian

AU - Schwartz, Ariel S.

AU - Semple, Colin A.

AU - Sera, Miho

AU - Severin, Jessica

AU - Shirahige, Katsuhiko

AU - Simons, Cas

AU - St. Laurent, George

AU - Suzuki, Masanori

AU - Suzuki, Takahiro

AU - Sweet, Matthew J.

AU - Taft, Ryan J.

AU - Takeda, Shizu

AU - Takenaka, Yoichi

AU - Tan, Kai

AU - Taylor, Martin S.

AU - Teasdale, Rohan D.

AU - Tegnér, Jesper

AU - Teichmann, Sarah

AU - Valen, Eivind

AU - Wahlestedt, Claes

AU - Waki, Kazunori

AU - Waterhouse, Andrew

AU - Wells, Christine A.

AU - Winther, Ole

AU - Wu, Linda

AU - Yamaguchi, Kazumi

AU - Yanagawa, Hiroshi

AU - Yasuda, Jun

AU - Zavolan, Mihaela

AU - Hume, David A.

AU - Arakawa, Takahiro

AU - Fukuda, Shiro

AU - Imamura, Kengo

AU - Kai, Chikatoshi

AU - Kaiho, Ai

AU - Kawashima, Tsugumi

AU - Kawazu, Chika

AU - Kitazume, Yayoi

AU - Kojima, Miki

AU - Miura, Hisashi

AU - Murakami, Kayoko

AU - Murata, Mitsuyoshi

AU - Ninomiya, Noriko

AU - Nishiyori, Hiromi

AU - Noma, Shohei

AU - Ogawa, Chihiro

AU - Sano, Takuma

AU - Simon, Christophe

AU - Tagami, Michihira

AU - Takahashi, Yukari

AU - Kawai, Jun

AU - Hayashizaki, Yoshihide

N1 - Funding Information: We thank A. Ambesi, H. Atsui, M. Bansal, V. Belcastro, H. Daub, D. di Bernardo, M. Furuya, A. Hasegawa, K. Hayashida, A. Hirakiyama, F. Hori, K. Koseki, S. Kuhara, N. Miyamoto, S. Miyano, M. Nishikawa, C. Ohinata, M. Persson, S. Saihara, C. Sakaba, H. Sano, E. Shibazaki, T. Takagi, K. Toyoda, Y. Tsujimura and M. Yamamoto for discussion, encouragement and technical assistance. We thank M. Muramatsu, T. Ogawa, Y. Sakaki and A. Wada for support and encouragement. This work was mainly supported by grants for the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan (Y.H.), Research Grant for the RIKEN Genome Exploration Research Project from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (Y.H.) and the RIKEN Frontier Research System, Functional RNA research program (Y.H.). A.R.R.F. is supported by a CJ Martin Fellowship from the Australian National Health and Medical Research Council (ID 428261). E.v.N. acknowledges support from SNF grant SNF #3100A0-118318.

PY - 2009/5

Y1 - 2009/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=65149083962&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65149083962&partnerID=8YFLogxK

U2 - 10.1038/ng.375

DO - 10.1038/ng.375

M3 - Article

C2 - 19377474

AN - SCOPUS:65149083962

SN - 1061-4036

VL - 41

SP - 553

EP - 562

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line

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