Lineages, cell types and functional states: a genomic view

Cellular differentiation progresses through an ordered cascade of events involving cell autonomous and micro-environment regulated expression or activation of transcription factors (TFs). Lineage-determining and stimulus-activated TFs collaborate in specifying the transcriptional programs of differentiating cells through the establishment of appropriate genomic repertoires of active or poised cis-regulatory elements, which can eventually be altered by environmental changes to generate transient or persistent functional states. Here, we rationalize available genomic and functional data into a mechanistic model whereby terminal differentiation proceeds first through the establishment of a regulatory landscape that is broadly shared among all cell types within a given lineage; and then through the selective activation of a more restricted set of regulatory elements that specify the unique transcriptional outputs of individual cell types. In this scheme, the interplay between cell-autonomous and microenvironment-regulated TFs is highly complex, with several documented variants.