Collective dynamics of specific gene ensembles crucial for neutrophil differentiation: the existence of genome vehicles revealed.
Cell fate decision remarkably generates specific cell differentiation path among the multiple possibilities that can arise through the complex interplay of high-dimensional genome activities. The coordinated action of thousands of genes to switch cell fate decision has indicated the existence of stable attractors guiding the process. However, origins of the intracellular mechanisms that create "cellular attractor" still remain unknown. Here, we examined the collective behavior of genome-wide expressions for neutrophil differentiation through two different stimuli, dimethyl sulfoxide (DMSO) and all-trans-retinoic acid (atRA). To overcome the difficulties of dealing with single gene expression noises, we grouped genes into ensembles and analyzed their expression dynamics in correlation space defined by Pearson correlation and mutual information. The standard deviation of correlation distributions of gene ensembles reduces when the ensemble size is increased following the inverse square root law, for both ensembles chosen randomly from whole genome and ranked according to expression variances across time. Choosing the ensemble size of 200 genes, we show the two probability distributions of correlations of randomly selected genes for atRA and DMSO responses overlapped after 48 hours, defining the neutrophil attractor. Next, tracking the ranked ensembles' trajectories, we noticed that only certain, not all, fall into the attractor in a fractal-like manner. The removal of these genome elements from the whole genomes, for both atRA and DMSO responses, destroys the attractor providing evidence for the existence of specific genome elements (named "genome vehicle") responsible for the neutrophil attractor. Notably, within the genome vehicles, genes with low or moderate expression changes, which are often considered noisy and insignificant, are essential components for the creation of the neutrophil attractor. Further investigations along with our findings might provide a comprehensive mechanistic view of cell fate decision.
Tsuchiya
Masa
M
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan. tsuchiya@ttck.keio.ac.jp
Piras
Vincent
V
Giuliani
Alessandro
A
Tomita
Masaru
M
Selvarajoo
Kumar
K
D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D017709:Fractals; D020869:Gene Expression Profiling; D016678:Genome / Q000235:genetics; D023281:Genomics / Q000379:methods*; D018922:HL-60 Cells; D006801:Humans; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011336:Probability; D014212:Tretinoin / Q000494:pharmacology
D014212:Tretinoin; D004121:Dimethyl Sulfoxide