The packaging of DNA on nucleosomes makes it more difficult for transcription factors to access DNA. This new study shows that these proteins have evolved several different mechanisms to get around the problem, allowing them to read the important messages in our genome that tell cells how to construct and maintain our tissues and organs.
The reported findings uncover a rich, interactive landscape between transcription factors and the nucleosome, thus paving a way to a thorough understanding of the complicated DNA decoding mechanisms in higher organisms. The findings also provide a basis for future studies aimed at understanding transcriptional regulation based on biochemical principles. As aberrant transcription factor activity is linked to many human diseases, including cancer, the findings are also relevant to understanding mechanisms of human disease.
We developed a massively parallel protein activity assay (Active Transcription Factor Identification, ATF) that can measure the DNA binding activity of all TFs in a particular cell type. By applying the technique to mouse tissues and embryonic stem cells, we found that only a small number of TFs demonstrated strong DNA binding in each of the tissues studied. These results suggest that, despite there being a huge number of TFs present in most tissues, just a handful of TFs may determine the gene expression landscape of a cell, and that the pattern of gene regulatory interactions may be far less complex and more hierarchical than previously thought.
Speaking about the research, Professor Jussi Taipale explained: "The finding that some transcription factors are much more active than others indicates that the regulatory system is far simpler than what we had imagined. We previously thought that all transcription factors can work together in millions of different ways to regulate genes. Instead, it now looks like weaker transcription factors need to work with the strong ones to get anything done. This makes the regulatory system very hierarchical, and simplifies the task of evolution. In a hierarchical system it is easier to evolve sets of co-expressed genes that work together to accomplish a particular task."