Mechanisms of long-range gene regulation in craniofacial development and disease

The almost identical faces of twins reveal that facial appearance is largely determined by our genetic make-up. We focus on understanding how one feature of the face, the lower jaw, is formed. Some babies are born with a jaw that is much smaller than in most children (a condition called PRS), which can be life threatening due to difficulties breathing. To study human jaw development and disease, we grow cells in a dish that are like cells that form the face in the womb. Changes to our DNA, called mutations, are mostly non-harmful and can contribute to differences in facial appearance between people. Some mutations can cause disease by damaging genes (instructions to make proteins). Surprisingly, many patient mutations (including those causing PRS) are located far away from genes, instead of within them, raising the question how these changes cause disease. We now understand that these non-gene mutations often break ‘switches’ that turn genes on and off. Many of the mutations that cause PRS break switches for an important face gene called SOX9. Interestingly, SOX9 has many switches which are unusually far away from the gene, and we are interested to understand how these switches work together across long distances. Ultimately, we hope to understand how genes are turned on and off normally, and how disruption can cause human disease. Our work will help to improve diagnosis and treatment options for patients and will have wide-reaching implications for many genetic conditions.