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

颅面发育和疾病的远程基因调控机制

• 批准号: MC_UU_00035/12
• 负责人: Hannah Long
• 金额: $ 302.37万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00035%2F12
• 关键词: Mechanisms; long; range; gene; regulation

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.

双胞胎的脸几乎一模一样，这表明面部外观在很大程度上是由我们的基因构成决定的。我们专注于了解面部特征（下颌）是如何形成的，有些婴儿出生时下颌就比下颌小得多。对于大多数儿童来说（一种称为 PRS 的疾病），这种疾病可能会因呼吸困难而危及生命。为了研究人类下巴的发育和疾病，我们在培养皿中培养了类似于子宫中形成面部的细胞。我们的 DNA 发生了变化。 ，称为突变，大多是无害的，并且可以一些突变会通过破坏基因（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，这引发了问题。这些变化如何导致疾病。我们现在了解到，这些非基因突变通常会“开关”基因，导致 PRS 破坏一种名为 SOX9 的重要面部基因。远离基因，我们有兴趣了解这些开关如何远距离协同工作。最终，我们希望了解基因如何正常打开和关闭，以及破坏如何导致人类疾病。我们的工作将有助于改善诊断。以及患者的治疗选择，将对许多遗传疾病产生广泛影响。

项目成果

Topology regulatory elements: From shaping genome architecture to gene regulation.

拓扑调控元件：从塑造基因组结构到基因调控。

• DOI: http://dx.10.1016/j.sbi.2023.102723
• 发表时间: 2023
• 期刊: Current opinion in structural biology
• 影响因子: 6.8
• 作者: Chen LF