A twist on developmental regulation of the face

February 1, 2024

By Christopher Vaughan

In many archives and libraries, storage space is used efficiently by putting bookshelves on tracks so that unused shelves can be squeezed tightly together. To retrieve a book, the shelves are rolled apart in one spot, leaving an opening for someone to walk in and access the particular shelf where the book is stored. 

DNA, the “book of life,” is likewise stored efficiently in the nucleus, packed tightly with proteins in a structure called chromatin. The tightly packed DNA in chromatin can’t normally be accessed and read by the cell’s protein-making machinery, but proteins called transcription factors can open up the chromatin, much as librarians can roll the shelves to make certain shelves accessible.

Researchers have long known about transcription factors that selectively open up the chromatin to access specific genes. The interplay between chromatin and various transcription factors allow cells to acquire separate identities during development. Now institute researchers in the laboratory of professor of chemical and systems biology and of developmental biology Joanna Wysocka, PhD have discovered a new DNA sequence element that modifies the action of transcription factors during development of the face. This element, called Coordinator, likely determines much of the fine tuning in gene expression that gives subtly different facial features to each individual.

“We know that face shape is highly heritable, and that the creation of these subtly different inherited facial features probably require extremely precise genetic control during development,” said Wysocka. “The question is where and how is this facial information coded?”

One challenge to understanding how subtle, inherited facial variations are encoded in DNA is the fact that the binding sites for so many of the know transcription factors are much the same. In order to have create so many facial variations, other factors are likely at play, Wysocka said. 

One way to increase the number of ways that transcription factors can affect cell behavior is to let different transcription factors coordinate with each other to affect what DNA gets read by the cell’s protein-making machinery. Such coordination can integrate functions performed by multiple transcription factors, and also confer regulatory specificity for selective pairs of transcription factors within large protein families.

Serendipitously, researchers in the Wysocka lab found a small DNA sequence that looked like it played a part in fulfilling such a role. Looking the facial development of chimpanzees and humans, species that share predominantly similar DNA but look very different, they found a 17 base-pair long DNA segment whose presence was far more predictive of those interspecies differences than sequences associated with any other transcription factor. They called the sequence “Coordinator,” and began looking for the transcription factors that might bind to it. 

Seungsoo Kim, PhD, a postdoctoral fellow in the Wysocka lab and the lead author of the study, showed that Coordinator sequences were able to associate with a transcription factor called TWIST1, which is known to be an important driver of cell identity during development. Coordinator sequences can hold other transcription factors (namely homedomain factors that determine the three dimensional organization of cells) close to TWIST1, creating a binary complex that exerted effects on genetic expression different than either transcription factor could exert individually. 

“Once TWIST1 and homeodomain transcription factor find the Coordinator sequence, it stabilizes the association between them, allowing for a stronger occupancy on chromatin and expression of target genes,” Wysocka said.

“Experiments have shown that this sort of “DNA-guided cooperativity” between transcription factors should be quite common in nature, but we have rarely seen it in action in developing organisms,” Wysocka said. “I suspect that as we look into this more, we will find more of these composite DNA motifs.”

In addition, Coordinator seem to be able to bring together two very different kinds of transcription factors—those associated with creating cell type identity (such as TWIST1) and those associated with determining where a certain cell positioned in a developing organism (such as homeodomain factors). “Obviously it’s important in any tissue that the right kinds of cells are created in the right places,” Wysocka said. “Sequences like coordinator could integrate cell lineage and positional information during the development of the face other tissues.” 

Of course, any development mechanisms can go astray. Wysocka and her colleagues think that some developmental disease will likely be found to be tied to the malfunction of Coordinator or other sequences involved in DNA-guided cooperativity. Understanding exactly how these sequences function and fail could lead to new treatments for those disorders, they said.