A handful of transcription factors confer a hierarchical gene expression landscape

The Taipale Group have published a new paper in Nature Biotechnology on the pattern of regulatory interactions involved in gene expression.

DNA contains the genetic information that all cells require to make the proteins and some other molecules that they need in order to grow, develop, reproduce and conduct their normal functions. Although almost every single cell in our bodies contains the exact same genetic information, not all our cells require all the proteins encoded within our DNA to perform their individual roles. Similarly, our cells do not need all of their proteins to be produced all of the time. In addition to genes that code for proteins, our DNA therefore also contains regulatory information that ensures the right genes are turned on for protein production in the right cells and at the right time.

Transcription factors (TFs) are a group of proteins that can read regulatory information within our DNA to determine which genes should be expressed and when. At the top level of this regulatory system, master TFs switch on genes that determine cell type. Genetic studies have previously found that there are relatively few of these master TFs,^1-3 with it being possible to reprogramme cells from one type to another by altering the expression of just one to five TFs.^4-6

Analyses by other techniques, such as gene expression profiling, proteomic analysis and chromatin immunoprecipitation followed by sequencing, have indicated that most tissues in fact express hundreds of TFs simultaneously. This suggests that regulatory control of gene expression, downstream from the few master TFs, is extremely complex and potentially involves a very large number of proteins and regulatory interactions. As these previous studies have, however, only analysed TF protein or RNA level, or measured the activity of a few TFs individually, it is unclear which TFs are the most active in different cell types.^7-10

In their new study, Wei et al. 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 their technique to mouse tissues and embryonic stem cells, the authors 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, senior author 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."

¹Boyer et al., Cell 122:947 (2005).

²Chen et al., Cell 133:1106 (2008).

³Wang et al., Nature 444:364 (2006).

⁴Takahashi and Yamanaka, Cell 126:663 (2006).

⁵Takahashi et al., Cell 131:861 (2007).

⁶Feng et al., Nat. Cell Bio. 11:197 (2009).

⁷Vaquerizas et al., Nat. Rev. Genet. 10:252 (2009).

⁸Uhlen et al., Science 347:1260419 (2015).

⁹Jolma et al., Cell 152:327 (2013).

¹⁰Consortium, Nature 489:57 (2012).