Abstract
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.
Highlights
System-wide analysis of the transcriptional network of human myelomonocytic leukemia cells predicts attractor structure and phorbol-ester-induced differentiation and dedifferentiation transitions
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
Our approach was: (i) eliminate irrelevant transcription factors (TFs) by filtering TFs based on www.nature.com/scientificreports covariance of temporal expression profiles; (ii) identify interactions connecting the filtered TFs based on goodness-of-fit and slope ratio information using a co-expression model; (iii) divide the filtered TFs based on the goodness-of-fit to the co-expression model; (iv) infer a system-wide structure in the identified interactions based on statistical significance of the interactions between two classes; and (v) simulate expression pattern transitions based on a transcriptional regulatory model deduced from the system-wide structure
Summary
System-wide analysis of the transcriptional network of human myelomonocytic leukemia cells predicts attractor structure and phorbol-ester-induced differentiation and dedifferentiation transitions. 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. Network dynamics have been examined based on relations between network motifs and dynamics[5], and coordination of signalling and transcriptional responses have been observed[6] Another approach, co-expression analysis, has been used to study functional gene modules[7,8,9,10]. We deduced a system-wide, ladder-like transcription factor cluster structure and validated predicted recurrent pattern transitions by state transition simulations
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