Robust global regulations of gene expression in biological processes: A major driver of cell fate decision revealed

One of the fundamental mysteries in biology is to grasp how a cell can choose a specific cellular process in coordinating complex multi-molecular interactions through DNA, RNA, proteins and metabolites. We investigated the existence of guiding principles in gene expression dynamics for three distinct processes: i) the innate immune response of macrophages to lipopolysaccharide (LPS) stimulation, ii) interleukin 12 (IL-12) and IL-4 stimulated naive CD4+ T cell differentiation into helper T1 and T2 cells, and iii) HL-60 cell differentiation into neutrophil. We found that for all processes, forming groups of genes reduces gene expression fluctuations, revealing the emergent hidden collective genome-wide (global) expression dynamics and their biological roles. This demonstrates an important role of lowly expressed genes, which have been considered insignificant and noisy, as key players for collective global dynamics. Moreover, in neutrophil differentiation, there are specific gene ensembles (collectively named “genome vehicle”) responsible for the cell fate, and the collective motion of lowly and moderately variable genes within the genome vehicle guides whole genome expression dynamics to the neutrophil cell state. Elucidation of biophysical origin for the global guiding principle might provide a breakthrough understanding of how a genome can control cellular processes such as cell fate and differentiation.