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

双胞胎几乎一模一样的脸表明，面部特征在很大程度上是由我们的基因组成决定的。我们专注于了解面部的一个特征，即下颌，是如何形成的。有些婴儿出生时下巴比大多数孩子小得多（这种情况称为PRS），由于呼吸困难，可能会危及生命。为了研究人类下巴的发育和疾病，我们在培养皿中培养细胞，就像子宫里形成面部的细胞一样。我们DNA的变化，也就是所谓的突变，大多是无害的，但会导致人与人之间的面部外观差异。一些突变可以通过破坏基因（制造蛋白质的指令）导致疾病。令人惊讶的是，许多患者突变（包括导致PRS的突变）位于远离基因的地方，而不是在基因内部，这就提出了这些变化是如何引起疾病的问题。我们现在知道，这些非基因突变通常会破坏基因的开关。许多导致PRS断裂的突变是一种重要的面部基因SOX9的开关。有趣的是，SOX9有许多开关离基因异常遥远，我们有兴趣了解这些开关是如何在远距离上协同工作的。最终，我们希望了解基因是如何正常开启和关闭的，以及基因的破坏是如何导致人类疾病的。我们的工作将有助于改善患者的诊断和治疗选择，并将对许多遗传疾病产生广泛的影响。

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.