Long ignored DNA segments affects earliest development of the face

Joanna Wysocka and Alvaro Rada Iglesias

By Christopher Vaughan


Epigenomic Annotation of Enhancers Predicts Transcriptional Regulators of Human Neural Crest.
Rada-Iglesias A, Bajpai R, Prescott S, Brugmann SA, Swigut T, Wysocka J.
Cell Stem Cell. 2012 Sep 12. pii: S1934-5909(12)00421-3. doi: 10.1016/j.stem.2012.07.006. [Epub ahead of print]
PMID: 22981823

Since there is not enough genetic information in the body to define exactly where each cell will go, development of the face proceeds much like origami: genes provide instructions for folding, crimping, and movement of cells. As with origami, following a set sequence of simple instructions can result in a complex and intricate object.   
Wysocka focused on the very first critical fold in the process of making an embryo, when the whole of the embryo is a flat sheet of cells that creases and closes over on itself to make a tube. Much of the tube eventually becomes the foundation of the brain and the spinal column, but one end sets the stage for the formation of the head and face. This process is driven by a small population of remarkable cells called neural crest cells. “We were interested in identifying the portions of the human genome are responsible for the behavior of the neural crest,” Wysocka says.
What they have discovered is that modification of a collection of DNA sequences called “enhancers” can dial up or down the activity of the genes that govern cells which eventually become the face. It’s almost as if they have discovered how the instructions for a beautiful piece of origami can be modified—slightly change how a fold is made and you may end up with something very different looking.
Of particular interest is the fact that although these enhancers affect how genes function, enhancers are not genes, nor are they always near the genes they affect. Enhancers exist in the vast non-coding regions of the genome that people used to call “junk DNA,” but which is now proving very important in genetic function. The enhancers can be silent or very active, depending on where a cell is and at what stage it is in the development of the embryo. “What’s really emerging is the idea that one cell type’s junk is another cell type’s treasure,” says Wysocka.
What’s useful about their discoveries is that that researchers will now know much better where to look for the causes of disorders of facial development like cleft lip or cleft palate. In these disorders, sheets of cells from opposite sides of the face do not fuse fully during development, leaving a cleft or gap. By identifying neural crest enhancers, our study can tell other investigators where to look for genetic variants that can explain these facial abnormalities or even why each human being has a unique face,” says Alvaro Rada Iglesias, who is the first author on the paper and a member of the Wysocka laboratory.”
Although only a handful of enhancers were already shown to be important in the regulation of early neural crest development, research by Wysocka and her colleagues has produced thousands of such enhancers that are active in determining the behavior of these cells. Moreover, this research showed that the information contained within those enhancers can be used to identify novel genes controlling neural crest and face formation.“Our results will serve as a resource for other investigators,” she says.
Wysocka expects that the usefulness of the data will extend far beyond facial development. By having the sequences of thousands of these enhancers, scientists can look at the kind of DNA patterns or “motifs” that are common in these enhancers and use that information to look for enhancers that regulate genes throughout development.

The human face is a fantastically intricate thing. The billions of people on the planet have faces that are individually recognizable because every person has subtle differences in the folds and curves that make up every face.
How is the face put together during development so that, out of billions of people, no two faces are exactly the same? Stanford researcher Joanna Wysocka and her colleagues have discovered key genetic elements that guide the earliest stages of the process. Their research, published in the journal Cell Stem Cell, provides a resource for others studying facial development and could give insights to the cause of some facial birth defects.

Top image is adapted from an illustration by Ernst Haekel, photo by C. Vaughan

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