The role of DNA Methylation, Chromatin Remodelling and Histone Modification in Syndromic and Non-Syndromic Congenital Heart Disease.

先天性心脏病（CHD）是出生时心脏结构的改变。作为最常见的出生缺陷，英国每年有超过4500名婴儿出生时患有冠心病。冠心病会对儿童造成重大影响，通常需要专科治疗或手术，并可能缩短寿命。我们知道，如果家庭中的其他人也受到影响，冠心病会更常见，但这种常见疾病的确切遗传原因仍未得到很好的了解。基因是指示身体如何生长发育的指令。它们是由我们身体细胞中的DNA组成的。细胞内的DNA是用一种叫做组蛋白的蛋白质来包装的：组蛋白可以用化学基团来标记（比如“甲基化”），这可以改变一个基因在身体每个细胞中的“开启”和“关闭”方式。有证据表明，所谓的“表观遗传”变化，如组蛋白甲基化，可能导致一定比例的冠心病病例。为了研究这一假设，我们从100,000基因组计划招募的近600个冠心病家庭中获得了非常详细的基因检测数据（全基因组测序数据）。此外，在之前的一项研究中，我们发现许多家庭中不止一个人患有冠心病。我们计划对这些家庭进行进一步、更详细的基因检测，以更好地了解冠心病的病因。一旦我们确定了冠心病的新原因，我们将使用疾病的细胞模型来证实我们的发现。该项目的第二部分将涉及对一种名为KMT2D的特定蛋白质的研究，这种蛋白质也参与组蛋白甲基化。我们发现这种蛋白与一种以冠心病为重要特征的新综合征有关。我们现在想研究这种蛋白质的基因变化或“突变”是如何导致如此严重的疾病的，以及它与冠心病的关系。我们将通过在干细胞中使用新的“基因编辑”工具来做到这一点，我们将用它来制作患者神经细胞的模型。然后，我们将研究这些细胞模型的具体特征，以及突变如何影响它们。这将使我们更好地了解KMT2D是如何工作的，并将其与冠心病联系起来。PI是一位经验丰富的临床遗传学家，对冠心病特别感兴趣，并拥有与冠心病相关的详细基因数据分析博士学位。因此，候选人具有拟议项目所需的经验和技能。PI将加入一个由CO-I领导的经验丰富的研究小组，该小组在这一领域取得了成功。他们利用最先进的技术，如新的基因编辑工具和新的细胞模型，研究人类疾病的遗传基础。候选人和研究小组得到了大学和医院信托基金的大力支持。自2013年以来，他们一直在项目上合作，可以为该项目带来互补的技能和经验，为临床和研究合作伙伴解决一个重要问题。发现冠心病的新遗传原因，了解冠心病和“组蛋白甲基化”之间的联系，将增加对形成胎儿心脏的详细过程的科学理解，以及这可能在疾病中受到影响的方式。这将有助于决定对冠心病的药物或手术治疗，因为我们怀疑患有不同遗传原因的冠心病患者对药物或手术的反应可能不同。因为我们正在研究的特定蛋白质组是重要的药物靶点，我们的科学研究可能对发现新药至关重要。该项目位于利兹的理想位置，未来5年将在利兹新建一所儿童医院，为最先进的患者护理、研究、培训和创新创造一个中心。

Congenital Heart Disease (CHD) is a change to the structure of the heart at birth. As the commonest birth defect, over 4,500 babies per year in the UK are born with CHD. CHD can cause a significant effect on a child, often needing specialist treatments or surgery, and can be associated with a shortened life-span. We know that CHD is more common if someone else in the family is also affected, but the exact genetic causes of this common condition are still not well understood. Genes are instructions to the body on how to grow and develop. They are made up of DNA in our body's cells. DNA inside cells is packaged using proteins called histones: these can be tagged by chemical groups (such as "methylation"), that can change how a gene is turned "on" and "off" in each cell of the body. There is some evidence to suggest that so-called "epigenetic" changes, such as histone methylation, can cause a proportion of CHD cases. To investigate this hypothesis, we have gained access to very detailed genetic testing data (Whole Genome Sequencing data) from nearly 600 families with CHD recruited to the 100,000 Genomes Project. Also, in a previous study, we identified a number of families where more than one individual had CHD. We plan to conduct further, more detailed genetic testing in these families, to understand better the cause of CHD. Once we have identified new causes of CHD, we will use cell models of disease to confirm our findings. The second part of the project will involve investigation of a specific protein, called KMT2D, which is also involved in histone methylation. We showed that this protein is associated with a new syndrome that has CHD as an important feature. We now want to investigate how a genetic change or "mutation" in this protein causes such severe disease, and how this links to CHD. We will do this by using new "gene-editing" tools in stem cells, which we will use to make a model of patient nerve cells. We will then investigate specific characteristics of these cell models, and how the mutations affect them. This will allow us to understand better how KMT2D works and to link this to CHD.The PI is an experienced Clinical Geneticist with a particular interest in CHD and a PhD in detailed genetic data analysis in relation to CHD. The candidate therefore has the experience and skills needed for the proposed project. The PI will join an experienced research group, led by the CO-I, with a proven track record of success in this field. They work with state-of-the-art technology, such as new gene-editing tools and novel cellular models, to investigate the genetic basis of human disease. The candidate and research group have strong support from the University and Hospital Trust. They have worked together on projects since 2013 and can bring complementary skills and experience to this project to tackle an important question for both the clinical and research partners. Finding new genetic causes of CHD and understanding the link between CHD and "histone methylation" will increase scientific understanding of the detailed processes involved in forming a fetal heart, and the ways in which this may be affected in disease. This will help in deciding upon medical or surgical managements for CHD, since we suspect that patients with different genetic causes of CHD may respond differently to medicines or surgery. Because the specific group of proteins we are studying are important drug targets, our scientific studies may be of key importance to discovering new drugs. This project is ideally placed in Leeds, where a new Children's Hospital is to be built over the next 5 years, to create a hub for state-of-the-art patient care, research, training and innovation.