Dynamic control of the T-cell specification gene regulatory network. Issue 18 (December 2019) - Rothenberg, Ellen V.
Abstract: Specification of multipotent blood precursor cells in postnatal mice to become committed T-cell precursors involves a gene regulatory network of several interacting but functionally distinct modules. Many links of this network have been defined by perturbation tests and by functional genomics. However, using the network model to predict real-life kinetics of the commitment process is still difficult, partly due to the tenacity of repressive chromatin states, and to the ability of transcription factors to affect each other's binding site choices through competitive recruitment to alternative sites ("coregulator theft"). To predict kinetics, future models will need to incorporate mechanistic information about chromatin state change dynamics and more sophisticated understanding of the proteomics and cooperative DNA site choices of transcription factor complexes. Highlights: A gene regulatory network model for T-cell specification is based on functional data. Five modules of regulatory genes are linked by defined, stage-dependent subcircuits. Pro-T cells also prime three latent network circuits that are normally suppressed. Actual system kinetics are also constrained by slow epigenetic state changes. Regulator genomic binding site choices are competitive, affected by other factors.