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.

双胞胎几乎相同的面孔表明，面部外观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，下颌，是如何形成的。有些婴儿出生时的下巴比大多数儿童小得多（这种情况称为PRS），由于呼吸困难，可能危及生命。为了研究人类颌骨的发育和疾病，我们在一个培养皿中培养细胞，这些细胞就像在子宫中形成面部的细胞一样。我们DNA的变化，称为突变，大多是无害的，可能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）引起疾病。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如何导致疾病的问题。我们现在知道，这些非基因突变通常会破坏打开和关闭基因的“开关”。许多导致PRS的突变破坏了一个重要的面部基因SOX 9的开关。有趣的是，SOX 9有许多开关，这些开关离基因非常远，我们有兴趣了解这些开关是如何在长距离内一起工作的。最终，我们希望了解基因是如何正常打开和关闭的，以及破坏如何导致人类疾病。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。

项目成果

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

• DOI: 10.1016/j.sbi.2023.102723
• 发表时间: 2023-12
• 期刊: Current opinion in structural biology
• 影响因子: 6.8
• 作者: Chen LF;Long HK
• 通讯作者: Long HK