UCLA

The human body is a patchwork of tissues working collectively to maintain homeostasis and achieve fitness objectives. Within these tissues are cells, the smallest units of life, which produce a tissue’s morphology through emergent behavior defined by a specific pattern of gene expression. However, the observation and interpretation of this behavior clash, creating serious contradictions that need to be resolved. Isogenic populations of cells exhibit significant phenotypic heterogeneity but are still treated as monolithic entities exhibiting homogenous behavior under equilibrium. Holding this contradiction together are theories of cell behavior that posit stochastic fluctuations as responsible for heterogeneity, treating it as different snapshots of a memoryless, dynamical, process. To test this theory, we’ve tested the persistence of distinct cellular states, such as the allele-specific variability of an exogenous reporter system and the intracellular calcium response to ATP, finding a lack of ergodicity. For the former we have also measured the co-fluctuation of underlying chromatin states, linking expression variability to variability in histone modifications. This work challenges existing paradigms of cellular heterogeneity, implying deeper regulation of cell state and more functionally stratified cell biology.