Feature-based classification of human transcription factors into hypothetical sub-classes related to regulatory function.

Background: Transcription factors are key proteins in the regulation of gene transcription. An important step in this process is the opening of chromatin in order to make genomic regions available for transcription. Data on DNase I hypersensitivity has previously been used to label a subset of transcription factors as Pioneers, Settlers and Migrants to describe their potential role in this process. These labels represent an interesting hypothesis on gene regulation and possibly a useful approach for data analysis, and therefore we wanted to expand the set of labeled transcription factors to include as many known factors as possible. We have used a well-annotated dataset of 1175 transcription factors as input to supervised machine learning methods, using the subset with previously assigned labels as training set. We then used the final classifier to label the additional transcription factors according to their potential role as Pioneers, Settlers and Migrants. The full set of labeled transcription factors was used to investigate associated properties and functions of each class, including an analysis of interaction data for transcription factors based on DNA co-binding and protein-protein interactions. We also used the assigned labels to analyze a previously published set of gene lists associated with a time course experiment on cell differentiation.

Results: The analysis showed that the classification of transcription factors with respect to their potential role in chromatin opening largely was determined by how they bind to DNA. Each subclass of transcription factors was enriched for properties that seemed to characterize the subclass relative to its role in gene regulation, with very general functions for Pioneers, whereas Migrants to a larger extent were associated with specific processes. Further analysis showed that the expanded classification is a useful resource for analyzing other datasets on transcription factors with respect to their potential role in gene regulation. The analysis of transcription factor interaction data showed complementary differences between the subclasses, where transcription factors labeled as Pioneers often interact with other transcription factors through DNA co-binding, whereas Migrants to a larger extent use protein-protein interactions. The analysis of time course data on cell differentiation indicated a shift in the regulatory program associated with Pioneer-like transcription factors during differentiation.

Conclusions: The expanded classification is an interesting resource for analyzing data on gene regulation, as illustrated here on transcription factor interaction data and data from a time course experiment. The potential regulatory function of transcription factors seems largely to be determined by how they bind DNA, but is also influenced by how they interact with each other through cooperativity and protein-protein interactions.