| Description |
The regulation of gene expression is central to cell biology. While gene expression is modulated at many levels, the interaction between DNA and sitespecific DNA binding transcription factors is a critical step. In metazoans, transcription factors usually exist in highly related families that exhibit a conserved preference for a particular DNA binding site. The ETS family provides a model for understanding how transcription factor families achieve distinct functions despite high conservation. With a focus on ETS1, genomic studies have identified two modes of ETS factor binding: redundant binding with other ETS factors, and specific binding of ETS1 only. The work presented in this dissertation uses genomic data from massively parallel sequencing experiments to refine the model of ETS factor occupancy in vivo. ETS-redundant and ETS1-specific binding events were found to be correlated with distinct recruitment motifs. ETS-redundant binding is co-incident with histone marks associated with active promoters while ETS1-specific binding is co-incident with histone marks associated with distal transcriptional enhancers. ETS1 co-localizes with the transcriptional co-activator CBP at enhancers, but not at promoters, suggesting different mechanisms of ETS1 function at these two recruitment sequences. Genome-wide disruption of ETS1 binding results in distinct expression profiles for genes near ETS-redundant and ETS1-specific binding events, confirming functional differences. At redundant promoters, disruption of ETS1 occupancy also provided the first example of dynamic time sharing by ETS1 and GABPA, establishing the molecular basis of redundancy within the ETS family. Unexpectedly, genes near ETS1-specific binding events were upregulated upon ETS1 disruption, suggesting a previously unidentified mode of regulation at these targets. These results serve as a framework for future studies investigating the specificity and redundancy of ETS factors in vivo. |
