Past Roadblocks and New Opportunities in Transcription Factor Network Mapping

One of the principal mechanisms by which cells differentiate and respond to changes in external signals or conditions is by changing the activity levels of transcription factors (TFs). This changes the transcription rates of target genes via the cell's TF network, which ultimately contributes to reconfiguring cellular state. Since microarrays provided our first window into global cellular state, computational biologists have eagerly attacked the problem of mapping TF networks, a key part of the cell's control circuitry. In retrospect, however, steady-state mRNA abundance levels were a poor substitute for TF activity levels and gene transcription rates. Likewise, mapping TF binding through chromatin immunoprecipitation proved less predictive of functional regulation and less amenable to systematic elucidation of complete networks than originally hoped. This review explains these roadblocks and the current, unprecedented blossoming of new experimental techniques built on second-generation sequencing, which hold out the promise of rapid progress in TF network mapping.