Computer-enhanced electron micrograph image of interacting chromatin chains in a cell nucleus. Image credit: Horng Ou, Sebastien Phan, Mark Ellisman, Clodagh O’Shea, Salk Institute, La Jolla, CA (CC BY-NC 2.0)
The human body is made up of about 200 different types of cells. Although all these cells contain the same genetic instructions in their DNA, each type performs specific functions. This is possible because different cells activate different sets of genes; for example, liver cells switch on genes specific to the liver, while blood cells turn on blood-specific genes.
Proteins known as transcription factors bind to DNA and activate specific genes, and they play a critical role in generating gene expression patterns that are unique to each cell type. Transcription factors are thought to be modular with two functional elements: DNA-binding domains that attach to genes, and activation domains that recruit the transcriptional machinery to switch on genes.
DNA-binding domains have traditionally been considered solely responsible for genome interaction. However, recent research indicates that short segments within the activation domain can also influence the transcription factors' affinity for DNA binding. To examine this, Fan et al. tracked individual transcription factor molecules in living cells and quantified the proportion bound to the genome.
The results confirmed that short activation domains play a major role in controlling the fraction of transcription factor molecules that bind to the genome. Strong activation domains – which interact robustly with coactivators or other components of the transcriptional machinery – increased the fraction of transcription-factor molecules bound to the genome. This effect was also achieved experimentally by strengthening otherwise regular activation domains through targeted mutation.
The study further demonstrated that activation domains tether transcription factors to the genome by binding to a coactivator already associated with chromatin, a protein that packages DNA into compact parcels. This binding may indirectly anchor the transcription factor to DNA even before its own DNA-binding domain engages.
Understanding how transcription factors bind the genome is essential for elucidating gene regulation. Traditional models assume that transcription factors first bind DNA through their DNA-binding domains and then use their activation domains to recruit the transcriptional machinery. The study of Fan et al. supports a model in which activation domains can instead bind coactivators that are already bound to DNA, tethering transcription factors indirectly to chromatin. These insights may ultimately deepen our understanding of gene regulation in development and disease.
