Differential variability and correlation of gene expression identifies key genes involved in neuronal differentiation

Tatsuya Ando, Ryuji Kato, Hiroyuki Honda

Understanding the dynamics of stem cell differentiation processes at the molecular level is a central challenge in developmental biology and regenerative medicine. Although the dynamic behaviors of differentiation regulators have been partially characterized, the architecture regulating the underlying molecular systems remains unclear. System-level analysis of transcriptional data was performed to characterize the dynamics of molecular networks in neural differentiation of stem cells. Expression of a network module of genes tightly co-expressed in mouse embryonic stem (ES) cells fluctuated greatly among cell populations before differentiation, but became stable following neural differentiation. During the neural differentiation process, genes exhibiting both differential variance and differential correlation between undifferentiated and differentiating states were related to developmental functions such as body axis development, neuronal movement, and transcriptional regulation. Furthermore, these genes were genetically associated with neuronal differentiation, providing support for the idea they are not only differentiation markers but could also play important roles in neural differentiation. Comparisons with transcriptional data from human induced pluripotent stem (iPS) cells revealed that the system of genes dynamically regulated during neural differentiation is conserved between mouse and human. The results of this study provide a systematic analytical framework for identifying key genes involved in neural differentiation by detecting their dynamical behaviors, as well as a basis for understanding the dynamic molecular mechanisms underlying the processes of neural differentiation.