System-wide analysis of the transcriptional network of human myelomonocytic leukemia cells predicts attractor structure and phorbol-ester-induced differentiation and dedifferentiation transitions

• Published in: Scientific reports Vol. 5; no. 1; p. 8283
• Main Authors: Sakata, Katsumi, Ohyanagi, Hajime, Sato, Shinji, Nobori, Hiroya, Hayashi, Akiko, Ishii, Hideshi, Daub, Carsten O., Kawai, Jun, Suzuki, Harukazu, Saito, Toshiyuki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.02.2015; Nature Publishing Group
• Subjects: 12-O-Tetradecanoylphorbol-13-acetate; 38/39; 631/114/2408; 631/553/2711; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Line, Tumor; Cell proliferation; Cluster Analysis; Computational Biology - methods; Gene Expression Regulation, Leukemic; Gene regulation; Gene Regulatory Networks; Genes; Humanities and Social Sciences; Humans; Leukemia; Leukemia, Myelomonocytic, Acute - genetics; Leukemia, Myelomonocytic, Acute - pathology; Mathematical models; Medicin och hälsovetenskap; Models, Biological; multidisciplinary; Myc protein; Myelomonocytic leukemia; Phorbol Esters - pharmacology; Pluripotency; Science; Stem cells; Transcription factors; Transcription, Genetic
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep08283

We present a system-wide transcriptional network structure that controls cell types in the context of expression pattern transitions that correspond to cell type transitions. Co-expression based analyses uncovered a system-wide, ladder-like transcription factor cluster structure composed of nearly 1,600 transcription factors in a human transcriptional network. Computer simulations based on a transcriptional regulatory model deduced from the system-wide, ladder-like transcription factor cluster structure reproduced expression pattern transitions when human THP-1 myelomonocytic leukaemia cells cease proliferation and differentiate under phorbol myristate acetate stimulation. The behaviour of MYC, a reprogramming Yamanaka factor that was suggested to be essential for induced pluripotent stem cells during dedifferentiation, could be interpreted based on the transcriptional regulation predicted by the system-wide, ladder-like transcription factor cluster structure. This study introduces a novel system-wide structure to transcriptional networks that provides new insights into network topology.