ELK1 Uses Different DNA Binding Modes to Regulate Functionally Distinct Classes of Target Genes

Abstract

Eukaryotic transcription factors are grouped into families and, due to their similar DNA binding domains, often have the potential to bind to the same genomic regions. This can lead to redundancy at the level of DNA binding, and mechanisms are required to generate specific functional outcomes that enable distinct gene expression programmes to be controlled by a particular transcription factor. Here we used ChIP–seq to uncover two distinct binding modes for the ETS transcription factor ELK1. In one mode, other ETS transcription factors can bind regulatory regions in a redundant fashion; in the second, ELK1 binds in a unique fashion to another set of genomic targets. Each binding mode is associated with different binding site features and also distinct regulatory outcomes. Furthermore, the type of binding mode also determines the control of functionally distinct subclasses of genes and hence the phenotypic response elicited. This is demonstrated for the unique binding mode where a novel role for ELK1 in controlling cell migration is revealed. We have therefore uncovered an unexpected link between the type of binding mode employed by a transcription factor, the subsequent gene regulatory mechanisms used, and the functional categories of target genes controlled.

Author Summary

One of the major outstanding questions in eukaryotic gene regulation is how transcription factors with seemingly very similar DNA binding specificities elicit specific biological responses. The ETS transcription factor family provides a paradigm for investigating this phenomenon. Here, we have focused on the ETS transcription factor ELK1, and by combining genome-wide binding analysis coupled with gene expression analysis we have dissected two distinct gene regulatory activities for this transcription factor. In each of these regulatory modes, ELK1 exhibits distinct DNA binding characteristics which correlate with either positive or negative transcriptional activities and give rise to functionally distinct gene expression programmes. We demonstrate a novel function for ELK1 in controlling cell migration through one of these regulatory modes. Thus, we have demonstrated a clear link between the types of regulatory region bound by a transcription factor and its ability to control gene expression (i.e. in a positive or negative manner) and the functional downstream consequences of its target gene cohort. This work has implications for understanding how members of other multi-protein transcription factor families might function to generate different downstream functional consequences through engaging with different types of regulatory regions.